Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures

• Published in: Nature communications 2020-05, Vol.11 (1), p.2393-13, Article 2393
• Main Authors: Vander Velde, Robert, Yoon, Nara, Marusyk, Viktoriya, Durmaz, Arda, Dhawan, Andrew, Miroshnychenko, Daria, Lozano-Peral, Diego, Desai, Bina, Balynska, Olena, Poleszhuk, Jan, Kenian, Liu, Teng, Mingxiang, Abazeed, Mohamed, Mian, Omar, Tan, Aik Choon, Haura, Eric, Scott, Jacob, Marusyk, Andriy
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/109; 13/31; 13/44; 14; 14/35; 14/56; 14/63; 38/23; 38/39; 38/88; 42; 45; 45/77; 59; 631/181/2475; 64; 64/60; 692/4028/67/1612/1350; 82/29; 96; Adaptation; Anaplastic Lymphoma Kinase - antagonists & inhibitors; Anaplastic Lymphoma Kinase - genetics; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epigenesis, Genetic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Humanities and Social Sciences; Humans; Inhibitors; Lapatinib - pharmacology; Lapatinib - therapeutic use; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mice; Molecular modelling; multidisciplinary; Non-small cell lung carcinoma; Polymorphism, Single Nucleotide - drug effects; RNA-Seq; Science; Science (multidisciplinary); Sensitivity; Single-Cell Analysis; Stochasticity; Subpopulations; Therapeutic applications; Tumor cells; Tumors; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16212-w

ABSTRACT Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance. Acquired resistance to cancer therapies reflects the ability of cancers to adapt to therapy-imposed selective pressures. Here, the authors elucidate the dynamics of developing resistance to ALK inhibitors in an ALK+ lung cancer cell line showing that resistance originates from drug-specific tolerant cancer cells and it develops as a gradual adaptation.