The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy.
This is a preview of subscription content
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).
Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304, 1497–1500 (2004).
Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).
Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).
Bergethon, K. et al. ROS1 rearrangements define a unique molecular class of lung cancers. J. Clin. Oncol. 30, 863–870 (2012).
Kohno, T. et al. KIF5B-RET fusions in lung adenocarcinoma. Nat. Med. 18, 375–377 (2012).
Vaishnavi, A. et al. Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat. Med. 19, 1469–1472 (2013).
Fernandez-Cuesta, L. et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov. 4, 415–422 (2014).
Marchetti, A. et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J. Clin. Oncol. 29, 3574–3579 (2011).
Paik, P. K. et al. Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations. J. Clin. Oncol. 29, 2046–2051 (2011).
Nieto, P. et al. A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 548, 239–243 (2017).
Stephens, P. et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004).
Ma, P. C. et al. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 65, 1479–1488 (2005).
Kong-Beltran, M. et al. Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res. 66, 283–289 (2006).
Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015).
Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).
Zhou, C. et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12, 735–742 (2011).
Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13, 239–246 (2012).
Yang, J. C. et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 16, 141–151 (2015).
Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018).
Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017).
Mok, T. S. et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J. Clin. Oncol. 36, 2244–2250 (2018).
Peters, S. et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017).
Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014).
Soria, J. C. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389, 917–929 (2017).
Camidge, D. R. et al. Brigatinib versus crizotinib in ALK-positive non–small-cell lung cancer. N. Engl. J. Med. 379, 2027–2039 (2018).
Solomon, B. J. et al. Lorlatinib in patients with ALK-positive non-small-cell lung cancer: results from a global phase 2 study. Lancet Oncol. 19, 1654–1667 (2018).
Planchard, D. et al. Dabrafenib plus trametinib in patients with previously untreated BRAF(V600E)-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 18, 1307–1316 (2017).
Mitsudomi, T. et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 11, 121–128 (2010).
Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).
Sequist, L. V. et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J. Clin. Oncol. 31, 3327–3334 (2013).
Ramalingam, S. S. et al. Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial. Lancet Oncol. 15, 1369–1378 (2014).
Rekhtman, N., Ang, D. C., Riely, G. J., Ladanyi, M. & Moreira, A. L. KRAS mutations are associated with solid growth pattern and tumor-infiltrating leukocytes in lung adenocarcinoma. Mod. Pathol. 26, 1307–1319 (2013).
Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014).
Shaw, A. T. et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N. Engl. J. Med. 371, 1963–1971 (2014).
Dueck, D. & Frey, B. J. Non-metric affinity propagation for unsupervised image categorization. 2007 IEEE 11th International Conference on Computer Vision 1-6, 198–205 (2007).
Kim, J. et al. XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer. Nature 538, 114–117 (2016).
Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).
Carbone, D. P. et al. First-line nivolumab in stage iv or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017).
Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).
Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).
Horn, L. et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J. Clin. Oncol. 35, 3924–3933 (2017).
Rittmeyer, A. et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389, 255–265 (2017).
Jackman, D. M. et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin. Cancer Res. 12, 3908–3914 (2006).
Choi, Y. W. et al. EGFR exon 19 deletion is associated with favorable overall survival after first-line gefitinib therapy in advanced non-small cell lung cancer patients. Am. J. Clin. Oncol. 41, 385–390 (2018).
Robichaux, J. P. et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat. Med. 24, 638–646 (2018).
Riess, J. W. et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J. Thorac. Oncol. 13, 1560–1568 (2018).
Childress, M. A. et al. ALK fusion partners impact response to ALK inhibition: differential effects on sensitivity, cellular phenotypes, and biochemical properties. Mol. Cancer Res. 16, 1724–1736 (2018).
Lin, J. J. et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J. Clin. Oncol. 36, 1199–1206 (2018).
Drilon, A. et al. A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105. Cancer Discov. 9, 384–395 (2019).
Ihle, N. T. et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J. Natl Cancer. Inst. 104, 228–239 (2012).
Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017).
Shepherd, F. A. et al. Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J. Clin. Oncol. 31, 2173–2181 (2013).
Yu, H. A. et al. Prognostic impact of KRAS mutation subtypes in 677 patients with metastatic lung adenocarcinomas. J. Thorac. Oncol. 10, 431–437 (2015).
Ostrem, J. M. & Shokat, K. M. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Discov. 15, 771–785 (2016).
Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).
Jordan, E. J. et al. prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017). This article and Frampton et al. (2015) are the largest reported studies of comprehensive genomic profiling in patients with advanced LUAD.
Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455, 1069–1075 (2008).
Campbell, J. D. et al. Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet. 48, 607–616 (2016).
Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).
Mina, M. et al. Conditional selection of genomic alterations dictates cancer evolution and oncogenic dependencies. Cancer Cell 32, 155–168 (2017). This study describes a novel algorithmic approach for assessment of cancer evolutionary dependencies and is the most comprehensive pancancer analysis of co-alteration patterns reported to date.
Campbell, P. J. Cliques and schisms of cancer genes. Cancer Cell 32, 129–130 (2017).
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD.
Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018). This study identifies inactivating LKB1 genomic alterations as a major driver of de novo resistance to PD-1 axis blockade in KRAS -mutant LUAD.
Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).
Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005).
Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumour suppressor genes. Genes Dev. 15, 3249–3262 (2001).
Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD.
Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling.
Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017). This landmark study establishes a census of clonal and subclonal alterations in early-stage NSCLC and identifies copy number heterogeneity as an independent predictor of short relapse-free survival following surgical resection.
Ortmann, C. A. et al. Effect of mutation order on myeloproliferative neoplasms. N. Engl. J. Med. 372, 601–612 (2015).
Swanton, C. Cancer evolution constrained by mutation order. N. Engl. J. Med. 372, 661–663 (2015).
Henderson, S., Chakravarthy, A., Su, X., Boshoff, C. & Fenton, T. R. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumour development. Cell Rep. 7, 1833–1841 (2014).
Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346, 256–259 (2014).
de Bruin, E. C. et al. Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346, 251–256 (2014).
Marty, R. et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell 171, 1272–1283 (2017). e15.
Brunet, J. P., Tamayo, P., Golub, T. R. & Mesirov, J. P. Metagenes and molecular pattern discovery using matrix factorization. Proc. Natl Acad. Sci. USA 101, 4164–4169 (2004).
Devarajan, K. Nonnegative matrix factorization: an analytical and interpretive tool in computational biology. PLOS Comput. Biol 4, e1000029 (2008).
Monti, S., Tamayo, P., Mesirov, J. & Golub, T. Consensus clustering: A resampling-based method for class discovery and visualization of gene expression microarray data. Mach. Learn. 52, 91–118 (2003).
Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007).
Li, F. et al. LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response. Cancer Cell 27, 698–711 (2015).
Zhang, H. et al. Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb repressive complex 2. Nat. Commun. 8, 14922 (2017).
Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumourigenesis. Nature 539, 390–395 (2016).
Liu, Y. et al. Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. Cancer Discov. 3, 870–879 (2013).
Kim, J. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168–172 (2017). This article identifies a co-mutation-specific metabolic dependence of KRAS ; LKB1 co-altered cells on the urea cycle enzyme CPS1 in order to maintain pyrimidine pools.
Yuan, T. L. et al. Differential effector engagement by oncogenic KRAS. Cell Rep. 22, 1889–1902 (2018).
Jaramillo, M. C. & Zhang, D. D. The emerging role of the Nrf2-Keap1 signalling pathway in cancer. Genes Dev. 27, 2179–2191 (2013).
Babur, O. et al. Systematic identification of cancer driving signalling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 16, 45 (2015).
Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017).
Singh, A. et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumourigenesis. J. Clin. Invest. 123, 2921–2934 (2013).
DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumourigenesis. Nature 475, 106–109 (2011).
DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small-cell lung cancer. Nat. Genet. 47, 1475–1481 (2015).
Galan-Cobo, A. et al. LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-mutant lung adenocarcinoma. Cancer Res. 79, 3251–3267 (2019).
Ying, H. et al. Oncogenic Kras maintains pancreatic tumours through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).
Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012).
Arbour, K. C. et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24, 334–340 (2018).
Feldser, D. M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572–575 (2010).
Junttila, M. R. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567–571 (2010).
Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016).
Nahar, R. et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun. 9, 216 (2018). This article provides a comprehensive evaluation of the clonal and subclonal genomic landscape of early-stage EGFR -mutant LUAD in patients of Asian descent.
Schmitt, A. et al. ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma. Cancer Res. 77, 3040–3056 (2017).
Petersen, L. F. et al. Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC. Oncotarget 8, 38326–38336 (2017).
Bechara, E. G., Sebestyen, E., Bernardis, I., Eyras, E. & Valcarcel, J. RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Mol. Cell 52, 720–733 (2013).
Zhao, J. et al. Functional analysis reveals that RBM10 mutations contribute to lung adenocarcinoma pathogenesis by deregulating splicing. Sci. Rep. 7, 40488 (2017).
Rogers, Z. N. et al. Mapping the in vivo fitness landscape of lung adenocarcinoma tumour suppression in mice. Nat. Genet. 50, 483–486 (2018). This study describes a novel in vivo platform for the rapid evaluation of the functional impact of co-occurring alterations in GEMMs of Kras -mutant LUAD.
Schuster, K. et al. Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis. Mol. Cancer Res. 12, 912–923 (2014).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Canale, M. et al. Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. Clin. Cancer Res. 23, 2195–2202 (2017).
Sato, S. et al. Impact of concurrent genomic alterations detected by comprehensive genomic sequencing on clinical outcomes in East-Asian patients with EGFR-mutated lung adenocarcinoma. Sci. Rep. 8, 1005 (2018).
VanderLaan, P. A. et al. Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes. Lung Cancer 106, 17–21 (2017).
Labbe, C. et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Lung Cancer 111, 23–29 (2017).
Kim, Y. et al. Concurrent genetic alterations predict the progression to target therapy in EGFR-mutated advanced nsclc. J. Thora.c Oncol. 14, 193–202 (2019).
Jakobsen, J. N., Santoni-Rugiu, E., Grauslund, M., Melchior, L. & Sorensen, J. B. Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment. Oncotarget 9, 26195–26208 (2018).
Lee, J. K. et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J. Clin. Oncol. 35, 3065–3074 (2017). This article reports that pre-existing co-alterations in TP53 and RB1 can predict transformation to small-cell carcinoma as a mechanism of acquired resistance to EGFR TKI therapy in EGFR -mutant LUAD.
Niederst, M. J. et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat. Commun. 6, 6377 (2015).
Marcoux, N. et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes. J. Clin. Oncol. 37, 278–285 (2019).
Nakayama, S. et al. β-catenin contributes to lung tumour development induced by EGFR mutations. Cancer Res. 74, 5891–5902 (2014).
Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016).
Pacheco-Pinedo, E. C. et al. Wnt/β-catenin signalling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium. J. Clin. Invest. 121, 1935–1945 (2011).
Eng, J. et al. Impact of concurrent PIK3CA mutations on response to EGFR tyrosine kinase inhibition in EGFR-mutant lung cancers and on prognosis in oncogene-driven lung adenocarcinomas. J. Thorac. Oncol. 10, 1713–1719 (2015).
Winslow, M. M. et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 473, 101–104 (2011).
Maeda, Y. et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J. Clin. Invest. 122, 4388–4400 (2012).
Yamaguchi, T. et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signalling in lung adenocarcinoma. Cancer Cell. 21, 348–361 (2012).
Lee, J. J. et al. Tracing oncogene rearrangements in the mutational history of lung adenocarcinoma. Cell 177, 1842–1857 (2019). e21.
Kron, A. et al. Impact of TP53 mutation status on systemic treatment outcome in ALK-rearranged non-small-cell lung cancer. Ann. Oncol. 29, 2068–2075 (2018).
Alidousty, C. et al. Genetic instability and recurrent MYC amplification in ALK-translocated NSCLC: a central role of TP53 mutations. J. Pathol. 246, 67–76 (2018).
Aisner, D. L. et al. The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC2). Clin. Cancer Res. 24, 1038–1047 (2018).
Michels, S. et al. Clinicopathological characteristics of RET rearranged lung cancer in European patients. J. Thorac. Oncol. 11, 122–127 (2016).
Kadara, H. et al. Whole-exome sequencing and immune profiling of early-stage lung adenocarcinoma with fully annotated clinical follow-up. Ann. Oncol. 28, 75–82 (2017).
Scheel, A. H. et al. PD-L1 expression in non-small-cell lung cancer: correlations with genetic alterations. Oncoimmunology 5, e1131379 (2016).
Cristescu, R. et al. Pan-tumour genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).
Koyama, S. et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumour microenvironment. Cancer Res. 76, 999–1008 (2016).
Kitajima, S. et al. Suppression of STING associated with LKB1 loss in KRAS-driven lung cancer. Cancer Discov. 9, 34–45 (2019). This is the first report that LKB1 loss results in impaired innate immune sensing of cytosolic DNA due to epigenetic repression of STING.
Partanen, J. I., Nieminen, A. I., Makela, T. P. & Klefstrom, J. Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc. Natl Acad. Sci. USA 104, 14694–14699 (2007).
Kortlever, R. M. et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell 171, 1301–1315.e14 (2017).
Gao, Y. et al. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc. Natl Acad. Sci. USA 107, 18892–18897 (2010).
Okon, I. S. et al. Protein kinase LKB1 promotes RAB7-mediated neuropilin-1 degradation to inhibit angiogenesis. J. Clin. Inves.t 124, 4590–4602 (2014).
Best, S. A. et al. Synergy between the KEAP1/NRF2 and PI3K pathways drives non-small-cell lung cancer with an altered immune microenvironment. Cell Metab. 27, 935–943.e4 (2018).
Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018).
Petitjean, A. et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumour phenotype: lessons from recent developments in the IARC TP53 database. Hum. Mutat. 28, 622–629 (2007).
Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumour mutational burden. Genome Med. 9, 34 (2017).
Cha, Y. J., Kim, H. R., Lee, C. Y., Cho, B. C. & Shim, H. S. Clinicopathological and prognostic significance of programmed cell death ligand-1 expression in lung adenocarcinoma and its relationship with p53 status. Lung Cancer 97, 73–80 (2016).
Meylan, E. et al. Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma. Nature 462, 104–107 (2009).
Dudnik, E. et al. BRAF mutant lung cancer: programmed death ligand 1 expression, tumour mutational burden, microsatellite instability status, and response to immune check-point inhibitors. J. Thorac. Oncol. 13, 1128–1137 (2018).
Negrao, M. et al. Driver mutations are associated with distinct patterns of response to immune checkpoint blockade in non-small cell lung cancer. J. Thorac. Oncol. 13, S733–S734 (2018).
Garnett, M. J. et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483, 570–575 (2012).
Barretina, J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
Basu, A. et al. An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules. Cell 154, 1151–1161 (2013).
Seashore-Ludlow, B. et al. Harnessing connectivity in a large-scale small-molecule sensitivity dataset. Cancer Discov. 5, 1210–1223 (2015).
Iorio, F. et al. A landscape of pharmacogenomic interactions in cancer. Cell 166, 740–754 (2016). This article reports that combinations of oncogenic alterations are better predictors of drug sensitivity than individual alterations.
Knijnenburg, T. A. et al. Logic models to predict continuous outputs based on binary inputs with an application to personalized cancer therapy. Sci. Rep. 6, 36812 (2016).
Kim, H. S. et al. Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell 155, 552–566 (2013). Together with McMillan et al. (2018), this article provides compelling evidence that co-occurring genomic alterations confer unique molecular dependencies and therapeutic vulnerabilities based on large scale chemical and genetic screens in panels of molecularly annotated NSCLC cell lines.
Shackelford, D. B. et al. LKB1 inactivation dictates therapeutic response of non-small-cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143–158 (2013).
Momcilovic, M. et al. Heightening energetic stress selectively targets LKB1-deficient non-small cell lung cancers. Cancer Res. 75, 4910–4922 (2015).
Inge, L. J. et al. LKB1 inactivation sensitizes non-small-cell lung cancer to pharmacological aggravation of ER stress. Cancer Lett. 352, 187–195 (2014).
Wang, J., Lohman, G. J. & Stubbe, J. Enhanced subunit interactions with gemcitabine-5′-diphosphate inhibit ribonucleotide reductases. Proc. Natl Acad. Sci. USA 104, 14324–14329 (2007).
Zegerman, P. & Diffley, J. F. DNA replication as a target of the DNA damage checkpoint. DNA Repair (Amst) 8, 1077–1088 (2009).
Liu, Y. et al. Gemcitabine and Chk1 inhibitor AZD7762 synergistically suppress the growth of Lkb1-deficient lung adenocarcinoma. Cancer Res. 77, 5068–5076 (2017).
Kim, N. et al. Cardiac glycosides display selective efficacy for STK11 mutant lung cancer. Sci. Rep. 6, 29721 (2016).
Chen, Z. et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613–617 (2012). This article first establishes the concept of the co-clinical trial and identifies that Lkb1 and Trp53 co-alterations can influence the clinical response of Kras -mutant lung cancer to chemotherapy and targeted therapy in mice.
Bonanno, L. et al. LKB1 expression correlates with increased survival in patients with advanced non-small cell lung cancer treated with chemotherapy and bevacizumab. Clin. Cancer Res. 23, 3316–3324 (2017).
McMillan, E. A. et al. Chemistry-first approach for nomination of personalized treatment in lung cancer. Cell 173, 864–878 (2018). e29 Together with Kim et al. (2013), this article provides compelling evidence that co-occurring genomic alterations confer unique molecular dependencies and therapeutic vulnerabilities on the basis of large-scale chemical and genetic screens in panels of molecularly annotated NSCLC cell lines.
Krall, E. B. et al. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife 6, e33173 (2017).
Skoulidis, F. et al. Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small-cell lung cancer. J. Clin. Oncol. 37, (15 Suppl.) 102 (2019).
Smida, M. et al. MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated. Nat. Commun. 7, 13701 (2016).
Torok, J. A. et al. Deletion of ATM in tumour but not endothelial cells improves radiation response in a primary mouse model of lung adenocarcinoma. Cancer Res. 79, 773–782 (2019).
Stites, E. C., Trampont, P. C., Haney, L. B., Walk, S. F. & Ravichandran, K. S. Cooperation between noncanonical ras network mutations. Cell Rep. 10, 840 (2015).
Hayashi, T. et al. RASA1 and NF1 are preferentially co-mutated and define a distinct genetic subset of smoking-associated non-small cell lung carcinomas sensitive to MEK inhibition. Clin. Cancer Res. 24, 1436–1447 (2018).
Kitajima, S. & Barbie, D. A. RASA1/NF1-mutant lung cancer: racing to the clinic? Clin. Cancer Res. 24, 1243–1245 (2018).
Lai, G. G. Y. et al. Clonal MET amplification as a determinant of tyrosine kinase inhibitor resistance in epidermal growth factor receptor-mutant non-small-cell lung cancer. J. Clin. Oncol. 37, 876–884 (2019).
Wu, S. G., Chang, Y. L., Yu, C. J., Yang, P. C. & Shih, J. Y. The role of PIK3CA mutations among lung adenocarcinoma patients with primary and acquired resistance to EGFR tyrosine kinase inhibition. Sci. Rep. 6, 35249 (2016).
Hellmann, M. D. et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 33, 843–852.e4 (2018).
Peng, W. et al. Loss of PTEN promotes resistance to t cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).
Sanchez-Vega, F. et al. Oncogenic signalling pathways in the cancer genome atlas. Cell 173, 321–337.e10 (2018).
Ellrott, K. et al. Scalable open science approach for mutation calling of tumour exomes using multiple genomic pipelines. Cell Syst. 6, 271–281.e7 (2018).
Hoadley, K. A. et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumours from 33 types of cancer. Cell 173, 291–304.e6 (2018).
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate - a practical and powerful approach to multiple testing. J. R. Stat. Soc. Series B Stat. Methodol. 57, 289–300 (1995).
Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer. 18, 139–147 (2018).
The authors acknowledge support from a Department of Defense Lung Cancer Research Program Career Development Award (W81XWH-16-1-0094 to F.S.), a RP160652 Cancer Prevention Research Institute of Texas Multi-Investigator Research Award (to J.V.H.), a NIH/NCI 1R01 CA205150 grant (to J.V.H.), Lung SPORE grant 5 P50 CA070907 and a Stand Up To Cancer–American Cancer Society Lung Cancer Dream Team Translational Research Grant (grant no. SU2C-AACR-DT17-15). Stand Up To Cancer is a programme of the Entertainment Industry Foundation and research grants are administered by the American Association for Cancer Research, the scientific partner of Stand Up To Cancer. In addition, the authors acknowledge generous philanthropic contributions to the University of Texas MD Anderson Lung Cancer Moonshots Program.
J.V.H. reports royalties and licensing fees from Spectrum Pharmaceuticals and Biotree; research support from AstraZeneca, Bayer, GlaxoSmithKline and Spectrum Pharmaceuticals; Advisory Committee membership from AstraZeneca, Boehringer-Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum Pharmaceuticals, EMD Serono and Synta Pharmaceuticals. F.S. reports honoraria from Bristol-Myers Squibb, outside the scope of this work and consultancy fees from Tango Therapeutics.
Peer review information
Nature Reviews Cancer thanks F. Hirsch, M. Ladanyi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Platinum-doublet chemotherapy
Cisplatin-based or carboplatin-based combinations with a second chemotherapeutic agent, most commonly pemetrexed (lung adenocarcinoma), taxanes (lung adenocarcinoma or lung squamous cell carcinoma) and gemcitabine (lung squamous cell carcinoma).
- Objective response
Measurable decrease in tumour burden of a predefined amount in response to therapy.
- Complete response
The disappearance of all signs of cancer in response to treatment, including both target and non-target lesions (with reduction of all lymph nodes to less than 10 mm in short axis), without emergence of any new lesions.
- Cold tumour immune microenvironment
Tumour microenvironment characterized by a lack or paucity of infiltrating T cells.
Conversion of one differentiated somatic cell type to another without passage through an intermediate pluripotent or progenitor cell state.
- Umbrella clinical trial
A clinical trial that assesses multiple targeted therapeutic strategies in a single cancer type.
About this article
Cite this article
Skoulidis, F., Heymach, J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer 19, 495–509 (2019). https://doi.org/10.1038/s41568-019-0179-8
Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression
Molecular Cancer (2022)
Long non-coding RNA LSAMP-1 is down-regulated in non-small cell lung cancer and predicts a poor prognosis
Cancer Cell International (2022)
Cell Death Discovery (2022)
A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers
Nature Communications (2022)
Nature Reviews Clinical Oncology (2022)