Therapeutic resistance continues to be an indominable foe in our ambition for curative cancer treatment. Recent insights into the molecular determinants of acquired treatment resistance in the clinical and experimental setting have challenged the widely held view of sequential genetic evolution as the primary cause of resistance and brought into sharp focus a range of non-genetic adaptive mechanisms. Notably, the genetic landscape of the tumour and the non-genetic mechanisms used to escape therapy are frequently linked. Remarkably, whereas some oncogenic mutations allow the cancer cells to rapidly adapt their transcriptional and/or metabolic programme to meet and survive the therapeutic pressure, other oncogenic drivers convey an inherent cellular plasticity to the cancer cell enabling lineage switching and/or the evasion of anticancer immunosurveillance. The prevalence and diverse array of non-genetic resistance mechanisms pose a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes. In this Perspective we discuss the key principles of non-genetic therapy resistance in cancer. We provide a perspective on the emerging data from clinical studies and sophisticated cancer models that have studied various non-genetic resistance pathways and highlight promising therapeutic avenues that may be used to negate and/or counteract the non-genetic adaptive pathways.
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.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Scott, A. M., Wolchok, J. D. & Old, L. J. Antibody therapy of cancer. Nat. Rev. Cancer 12, 278–287 (2012).
Mayes, P. A., Hance, K. W. & Hoos, A. The promise and challenges of immune agonist antibody development in cancer. Nat. Rev. Drug. Discov. 17, 509–527 (2018).
Smaglo, B. G., Aldeghaither, D. & Weiner, L. M. The development of immunoconjugates for targeted cancer therapy. Nat. Rev. Clin. Oncol. 11, 637–648 (2014).
Meric-Bernstam, F. & Mills, G. B. Overcoming implementation challenges of personalized cancer therapy. Nat. Rev. Clin. Oncol. 9, 542–548 (2012).
Fong, C. Y. et al. BET inhibitor resistance emerges from leukaemia stem cells. Nature 525, 538–542 (2015).
Kim, C. et al. Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing. Cell 173, 879–893.e13 (2018).
Pisco, A. O. & Huang, S. Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘What does not kill me strengthens me’. Br. J. Cancer 112, 1725–1732 (2015).
Shlush, L. I. et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature 547, 104–108 (2017).
Hugo, W. et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. Cell 162, 1271–1285 (2015).
Dobson, S. M. et al. Relapse-fated latent diagnosis subclones in acute B lineage leukemia are drug tolerant and possess distinct metabolic programs. Cancer Discov. 10, 568–587 (2020).
DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).
Nakasone, E. S. et al. Imaging tumor-stroma interactions during chemotherapy reveals contributions of the microenvironment to resistance. Cancer Cell 21, 488–503 (2012).
Rosenzweig, S. A. Acquired resistance to drugs targeting receptor tyrosine kinases. Biochem. Pharmacol. 83, 1041–1048 (2012).
Kim, T. K., Herbst, R. S. & Chen, L. Defining and understanding adaptive resistance in cancer immunotherapy. Trends Immunol. 39, 624–631 (2018).
Beltran, H. et al. Whole-exome sequencing of metastatic cancer and biomarkers of treatment response. JAMA Oncol. 1, 466–474 (2015).
Pogrebniak, K. L. & Curtis, C. Harnessing tumor evolution to circumvent resistance. Trends Genet. 34, 639–651 (2018).
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
Menon, D. R. et al. A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 34, 4545 (2015).
Dallas, N. A. et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 69, 1951–1957 (2009).
Xue, Z. et al. Identification of cancer stem cells in vincristine preconditioned SGC7901 gastric cancer cell line. J. Cell Biochem. 113, 302–312 (2012).
Pirozzi, G. et al. Epithelial to mesenchymal transition by TGFbeta-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS ONE 6, e21548 (2011).
Gupta, P. B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).
Polyak, K. & Weinberg, R. A. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat. Rev. Cancer 9, 265–273 (2009).
Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).
Hoek, K. S. & Goding, C. R. Cancer stem cells versus phenotype-switching in melanoma. Pigment Cell Melanoma Res. 23, 746–759 (2010).
Kemper, K., de Goeje, P. L., Peeper, D. S. & van Amerongen, R. Phenotype switching: tumor cell plasticity as a resistance mechanism and target for therapy. Cancer Res. 74, 5937–5941 (2014).
Shaffer, S. M. et al. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546, 431–435 (2017).
Rambow, F. et al. Toward minimal residual disease-directed therapy in melanoma. Cell 174, 843–855 e19 (2018).
Boshuizen, J. et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat. Med. 24, 203–212 (2018).
Lee, J. H. et al. Transcriptional downregulation of MHC class I and melanoma de- differentiation in resistance to PD-1 inhibition. Nat. Commun. 11, 1897 (2020).
Koyama, S. et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat. Commun. 7, 10501 (2016).
Fallahi-Sichani, M. et al. Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol. Syst. Biol. 13, 905 (2017).
Bigger, J. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244, 497–500 (1944).
Holden, D. W. Microbiology. Persisters unmasked. Science 347, 30–32 (2015).
Su, Y. et al. Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. Proc. Natl Acad. Sci. USA 114, 13679–13684 (2017).
Tsoi, J. et al. Multi-stage differentiation defines melanoma subtypes with differential vulnerability to drug-induced iron-dependent oxidative stress. Cancer Cell 33, 890–904.e5 (2018).
Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).
Garg, M. et al. Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. Blood 126, 2491–2501 (2015).
Li, S. et al. Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat. Med. 22, 792–799 (2016).
Shiba, N. et al. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. Br. J. Haematol. 175, 476–489 (2016).
Rizos, H. et al. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin. Cancer Res. 20, 1965–1977 (2014).
Shi, H. et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov. 4, 69–79 (2014).
Boumahdi, S. & de Sauvage, F. J. The great escape: tumour cell plasticity in resistance to targeted therapy. Nat. Rev. Drug Discov. 19, 39–56 (2020).
Bell, C. C. et al. Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia. Nat. Commun. 10, 2723 (2019).
Chen, A. F. et al. GRHL2-dependent enhancer switching maintains a pluripotent stem cell transcriptional subnetwork after exit from naive pluripotency. Cell Stem Cell 23, 226–238.e4 (2018).
Kieffer-Kwon, K. R. et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell 155, 1507–1520 (2013).
Iniguez, A. B. et al. Resistance to epigenetic-targeted therapy engenders tumor cell vulnerabilities associated with enhancer remodeling. Cancer Cell 34, 922–938.e7 (2018).
Hinohara, K. et al. KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance. Cancer Cell 34, 939–953.e9 (2018).
Liau, B. B. et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell 20, 233–246.e7 (2017).
Zawistowski, J. S. et al. Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. Cancer Discov. 7, 302–321 (2017).
Stergachis, A. B. et al. Developmental fate and cellular maturity encoded in human regulatory DNA landscapes. Cell 154, 888–903 (2013).
Pastushenko, I. et al. Identification of the tumour transition states occurring during EMT. Nature 556, 463–468 (2018).
Puisieux, A., Pommier, R. M., Morel, A. P. & Lavial, F. Cellular pliancy and the multistep process of tumorigenesis. Cancer Cell 33, 164–172 (2018).
Morel, A. P. et al. A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nat. Med. 23, 568–578 (2017).
Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380 (2017).
Sanchez-Danes, A. et al. A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Nature 562, 434–438 (2018).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Umkehrer, C. et al. Isolating live cell clones from barcoded populations using CRISPRa-inducible reporters. Nat. Biotechnol. https://doi.org/10.1038/s41587-020-0614-0 (2020).
Moudgil, A. et al. Self-reporting transposons enable simultaneous readout of gene expression and transcription factor binding in single cells. Cell 182, 992–1008.e21 (2020).
Weinreb, C., Rodriguez-Fraticelli, A., Camargo, F. D. & Klein, A. M. Lineage tracing on transcriptional landscapes links state to fate during differentiation. Science 367, eaaw3381 (2020).
Russo, M. et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science 366, 1473–1480 (2019).
Cipponi, A. et al. MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer. Science 368, 1127–1131 (2020).
Kadoch, C. Diverse compositions and functions of chromatin remodeling machines in cancer. Sci. Transl Med. 11, eaay1018 (2019).
Agarwal, R. et al. Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. Nat. Med. 25, 119–129 (2019).
Xu, G. et al. ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer. Nat. Genet. 52, 198–207 (2020).
Nagarajan, S. et al. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat. Genet. 52, 187–197 (2020).
Quintanal-Villalonga, A. et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 17, 360–371 (2020).
Oser, M. G., Niederst, M. J., Sequist, L. V. & Engelman, J. A. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 16, e165–e172 (2015).
Davies, A. H., Beltran, H. & Zoubeidi, A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat. Rev. Urol. 15, 271–286 (2018).
Biehs, B. et al. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature 562, 429–433 (2018).
Sutherland, K. D. et al. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer Cell 19, 754–764 (2011).
Sutherland, K. D. et al. Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma. Proc. Natl Acad. Sci. USA 111, 4952–4957 (2014).
Lin, C. et al. Alveolar type II cells possess the capability of initiating lung tumor development. PLoS ONE 7, e53817 (2012).
George, J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 524, 47–53 (2015).
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).
Imielinski, M. et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107–1120 (2012).
Miettinen, P. J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl Med. 3, 75ra26 (2011).
Takegawa, N. et al. Transformation of ALK rearrangement-positive adenocarcinoma to small-cell lung cancer in association with acquired resistance to alectinib. Ann. Oncol. 27, 953–955 (2016).
Adelstein, D. J., Tomashefski, J. F. Jr. Snow, N. J., Horrigan, T. P. & Hines, J. D. Mixed small cell and non-small cell lung cancer. Chest 89, 699–704 (1986).
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).
Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).
Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).
Walter, D. M. et al. RB constrains lineage fidelity and multiple stages of tumour progression and metastasis. Nature 569, 423–427 (2019).
Park, J. W. et al. Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage. Science 362, 91–95 (2018).
Dardenne, E. et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 30, 563–577 (2016).
Burr, M. L. et al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell 36, 385–401.e8 (2019).
Bernards, R., Dessain, S. K. & Weinberg, R. A. N-myc amplification causes down-modulation of MHC class I antigen expression in neuroblastoma. Cell 47, 667–674 (1986).
Restifo, N. P. et al. Identification of human cancers deficient in antigen processing. J. Exp. Med. 177, 265–272 (1993).
Paulson, K. G. et al. Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. Nat. Commun. 9, 3868 (2018).
Agudo, J. et al. Quiescent tissue stem cells evade immune surveillance. Immunity 48, 271–285.e5 (2018).
Landsberg, J. et al. Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation. Nature 490, 412–416 (2012).
Mehta, A. et al. Immunotherapy resistance by inflammation-induced dedifferentiation. Cancer Discov. 8, 935–943 (2018).
Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219–1226 (2018).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Maude, S. L. et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. J. Clin. Oncol. 34, 3011–3011 (2016).
Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).
Gardner, R. et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127, 2406–2410 (2016).
Turtle, C. J. et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016).
Andersson, A. K. et al. The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nat. Genet. 47, 330–337 (2015).
The Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 368, 2059–2074 (2013).
Greaves, M. When one mutation is all it takes. Cancer Cell 27, 433–434 (2015).
Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006).
Jacoby, E. et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat. Commun. 7, 12320 (2016).
Zoghbi, A., Zur Stadt, U., Winkler, B., Muller, I. & Escherich, G. Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement. Pediatr. Blood Cancer 64, e26594 (2017).
Rayes, A., McMasters, R. L. & O’Brien, M. M. Lineage switch in MLL-rearranged infant leukemia following CD19-directed therapy. Pediatr. Blood Cancer 63, 1113–1115 (2016).
Xue, Y. et al. An approach to suppress the evolution of resistance in BRAF(V600E)-mutant cancer. Nat. Med. 23, 929–937 (2017).
Greaves, M. Evolutionary determinants of cancer. Cancer Discov. 5, 806–820 (2015).
McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).
Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).
Chong, C. R. & Janne, P. A. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat. Med. 19, 1389–1400 (2013).
Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015).
Siravegna, G. et al. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients. Nat. Med. 21, 827 (2015).
Diaz, L. A. Jr. et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486, 537–540 (2012).
Miller, T. W., Balko, J. M. & Arteaga, C. L. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J. Clin. Oncol. 29, 4452–4461 (2011).
Christie, E. L. et al. Reversion of BRCA1/2 germline mutations detected in circulating tumor DNA from patients with high-grade serous ovarian cancer. J. Clin. Oncol. 35, 1274–1280 (2017).
Tirosh, I. et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352, 189–196 (2016).
van Galen, P. et al. Single-cell RNA-Seq reveals AML hierarchies relevant to disease progression and immunity. Cell 176, 1265–1281.e24 (2019).
Miyamoto, D. T. et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 349, 1351–1356 (2015).
Cheng, Y. H. et al. Hydro-Seq enables contamination-free high-throughput single-cell RNA-sequencing for circulating tumor cells. Nat. Commun. 10, 2163 (2019).
Baryawno, N. et al. A cellular taxonomy of the bone marrow stroma in homeostasis and leukemia. Cell 177, 1915–1932.e16 (2019).
Rodriguez-Meira, A. et al. Unravelling intratumoral heterogeneity through high-sensitivity single-cell mutational analysis and parallel RNA sequencing. Mol. Cell 73, 1292–1305.e8 (2019).
Macaulay, I. C., Ponting, C. P. & Voet, T. Single-cell multiomics: multiple measurements from single cells. Trends Genet. 33, 155–168 (2017).
Rozenblatt-Rosen, O. et al. The human tumor atlas network: charting tumor transitions across space and time at single-cell resolution. Cell 181, 236–249 (2020).
Tung, P. Y. et al. Batch effects and the effective design of single-cell gene expression studies. Sci. Rep. 7, 39921 (2017).
Stahl, P. L. et al. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science 353, 78–82 (2016).
Wang, X. et al. Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science 361, eaat5691 (2018).
Ke, R. et al. In situ sequencing for RNA analysis in preserved tissue and cells. Nat. Methods 10, 857–860 (2013).
Svedlund, J. et al. Generation of in situ sequencing based OncoMaps to spatially resolve gene expression profiles of diagnostic and prognostic markers in breast cancer. EBioMedicine 48, 212–223 (2019).
Xia, C., Fan, J., Emanuel, G., Hao, J. & Zhuang, X. Spatial transcriptome profiling by MERFISH reveals subcellular RNA compartmentalization and cell cycle-dependent gene expression. Proc. Natl Acad. Sci. USA 116, 19490–19499 (2019).
Rapino, F. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558, 605–609 (2018).
Garcia-Jimenez, C. & Goding, C. R. Starvation and pseudo-starvation as drivers of cancer metastasis through translation reprogramming. Cell Metab. 29, 254–267 (2019).
Jewer, M. et al. Translational control of breast cancer plasticity. Nat. Commun. 11, 2498 (2020).
Giesen, C. et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat. Methods 11, 417–422 (2014).
Jackson, H. W. et al. The single-cell pathology landscape of breast cancer. Nature 578, 615–620 (2020).
Schulz, D. et al. Simultaneous multiplexed imaging of mRNA and proteins with subcellular resolution in breast cancer tissue samples by mass cytometry. Cell Syst. 6, 25–36.e5 (2018).
Saez-Ayala, M. et al. Directed phenotype switching as an effective antimelanoma strategy. Cancer Cell 24, 105–119 (2013).
Das Thakur, M. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013).
Venkatesh, V. et al. Targeting Notch signalling pathway of cancer stem cells. Stem Cell Investig. 5, 5 (2018).
Amakye, D., Jagani, Z. & Dorsch, M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nat. Med. 19, 1410–1422 (2013).
Nusse, R. & Clevers, H. Wnt/beta-catenin signaling, disease, and emerging therapeutic modalities. Cell 169, 985–999 (2017).
MacPherson, L. et al. HBO1 is required for the maintenance of leukaemia stem cells. Nature 577, 266–270 (2020).
Uckelmann, H. J. et al. Therapeutic targeting of preleukemia cells in a mouse model of NPM1 mutant acute myeloid leukemia. Science 367, 586–590 (2020).
Codd, A. S., Kanaseki, T., Torigo, T. & Tabi, Z. Cancer stem cells as targets for immunotherapy. Immunology 153, 304–314 (2018).
Shi, Y., Du, L., Lin, L. & Wang, Y. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat. Rev. Drug Discov. 16, 35–52 (2017).
Friedmann Angeli, J. P., Krysko, D. V. & Conrad, M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat. Rev. Cancer 19, 405–414 (2019).
Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).
Hangauer, M. J. et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551, 247–250 (2017).
Kinsey, C. G. et al. Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 25, 620–627 (2019).
Roesch, A. et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell 23, 811–825 (2013).
McConkey, D. J. The integrated stress response and proteotoxicity in cancer therapy. Biochem. Biophys. Res. Commun. 482, 450–453 (2017).
Rzymski, T., Milani, M., Singleton, D. C. & Harris, A. L. Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia. Cell Cycle 8, 3838–3847 (2009).
Falletta, P. et al. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes. Dev. 31, 18–33 (2017).
Shlyueva, D., Stampfel, G. & Stark, A. Transcriptional enhancers: from properties to genome-wide predictions. Nat. Rev. Genet. 15, 272–286 (2014).
Corces, M. R. et al. The chromatin accessibility landscape of primary human cancers. Science 362, eaav1898 (2018).
Salami, J. & Crews, C. M. Waste disposal-an attractive strategy for cancer therapy. Science 355, 1163–1167 (2017).
Michalak, E. M., Burr, M. L., Bannister, A. J. & Dawson, M. A. The roles of DNA, RNA and histone methylation in ageing and cancer. Nat. Rev. Mol. Cell Biol. 20, 573–589 (2019).
Tyler, D. S. et al. Click chemistry enables preclinical evaluation of targeted epigenetic therapies. Science 356, 1397–1401 (2017).
Dawson, M. A. The cancer epigenome: concepts, challenges, and therapeutic opportunities. Science 355, 1147–1152 (2017).
Sharma, A. et al. Longitudinal single-cell RNA sequencing of patient-derived primary cells reveals drug-induced infidelity in stem cell hierarchy. Nat. Commun. 9, 4931 (2018).
Knoechel, B. et al. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Nat. Genet. 46, 364–370 (2014).
Wei, A. H. et al. The QUAZAR AML-001 maintenance trial: results of a phase III international, randomized, double-blind, placebo-controlled study of CC-486 (oral formulation of azacitidine) in patients with acute myeloid leukemia (AML) in first remission. Blood 134, LBA-3 (2019).
Nowell, P. C. The clonal evolution of tumor cell populations. Science 194, 23–28 (1976).
Gerlinger, M. et al. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nat. Genet. 46, 225–233 (2014).
Morrissy, A. S. et al. Spatial heterogeneity in medulloblastoma. Nat. Genet. 49, 780–788 (2017).
Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).
Hu, Z., Li, Z., Ma, Z. & Curtis, C. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nat. Genet. 52, 701–708 (2020).
Patch, A. M. et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521, 489–494 (2015).
Savas, P. et al. The subclonal architecture of metastatic breast cancer: results from a prospective community-based rapid autopsy program “CASCADE”. PLoS Med. 13, e1002204 (2016).
Chen, J. et al. Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level. Nat. Med. 25, 103–110 (2019).
Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature 545, 446–451 (2017).
Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).
Scherer, F. et al. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci. Transl Med. 8, 364ra155 (2016).
Yeh, P. et al. Circulating tumour DNA reflects treatment response and clonal evolution in chronic lymphocytic leukaemia. Nat. Commun. 8, 14756 (2017).
The authors thank all the members of the J.-C.M., S.-J.D. and M.A.D laboratories for helpful discussions related to the concepts presents in this Perspective. The authors thank N. Dawson for help with figure construction and graphical illustrations. The authors thank the following funders for support: Cancer Council Victoria for a Sir Edward Dunlop Research Fellowship and Howard Hughes Medical Institute for an international research scholarship (M.A.D) and CSL for a CSL Centenary Fellowship (S.-J.D).
M.A.D. has been a member of advisory boards for Cancer Therapeutics CRC, Storm Therapeutics, Celgene and Cambridge Epigenetix. S.-J.D. has been a member of the advisory board for AstraZeneca. The S.-J.D. laboratory has received research funding from Genentech. The M.A.D. and S.-J.D. laboratories receive research funding from Cancer Therapeutics CRC. J.-C.M. declares no competing interests.
Peer review information
Nature Reviews Cancer thanks J. Carroll, U. McDermott 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.
About this article
Cite this article
Marine, JC., Dawson, SJ. & Dawson, M.A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat Rev Cancer 20, 743–756 (2020). https://doi.org/10.1038/s41568-020-00302-4
SATB2 induction of a neural crest mesenchyme-like program drives melanoma invasion and drug resistance
Rapid isolation of circulating cancer associated fibroblasts by acoustic microstreaming for assessing metastatic propensity of breast cancer patients
Lab on a Chip (2021)
Critical Reviews in Biochemistry and Molecular Biology (2021)
Feed‐forward activation of STAT3 signaling limits the efficacy of c‐Met inhibitors in esophageal squamous cell carcinoma (ESCC) treatment
Molecular Carcinogenesis (2021)
Cancer Research (2021)