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Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy

Abstract

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.

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Fig. 1: Single oncogenic driver paradigm of lung adenocarcinoma molecular classification.
Fig. 2: Spectrum of major co-occurring genomic alterations in KRAS-mutant and EGFR-mutant lung adenocarcinoma.
Fig. 3: Impact of co-mutations on the microenvironment of KRAS-mutant lung adenocarcinoma.
Fig. 4: Next-generation model for the molecular stratification of lung adenocarcinoma.

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Acknowledgements

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.

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F.S. researched data for article, substantially contributed to discussion of the content, wrote the article, and reviewed and edited the manuscript before submission. J.V.H. substantially contributed to discussion of the content, and reviewed and edited the manuscript before submission.

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Correspondence to Ferdinandos Skoulidis.

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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.

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Nature Reviews Cancer thanks F. Hirsch, M. Ladanyi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

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.

Transdifferentiation

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.

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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

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