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

Robert Vander Velde, Nara Yoon, Viktoriya Marusyk, Arda Durmaz, Andrew Dhawan, Daria Miroshnychenko, Diego Lozano-Peral, Bina Desai, Olena Balynska, Jan Poleszhuk, Liu Kenian, Mingxiang Teng, Mohamed Abazeed, Omar Mian, Aik Choon Tan, Eric Haura, Jacob Scott () and Andriy Marusyk ()
Additional contact information
Robert Vander Velde: H Lee Moffitt Cancer Centre and Research Institute
Nara Yoon: Cleveland Clinic
Viktoriya Marusyk: H Lee Moffitt Cancer Centre and Research Institute
Arda Durmaz: Cleveland Clinic
Andrew Dhawan: Cleveland Clinic
Daria Miroshnychenko: H Lee Moffitt Cancer Centre and Research Institute
Diego Lozano-Peral: H Lee Moffitt Cancer Centre and Research Institute
Bina Desai: H Lee Moffitt Cancer Centre and Research Institute
Olena Balynska: H Lee Moffitt Cancer Centre and Research Institute
Jan Poleszhuk: Polish Academy of Sciences
Liu Kenian: H Lee Moffitt Cancer Centre and Research Institute
Mingxiang Teng: H Lee Moffitt Cancer Centre and Research Institute
Mohamed Abazeed: Cleveland Clinic
Omar Mian: Cleveland Clinic
Aik Choon Tan: H Lee Moffitt Cancer Centre and Research Institute
Eric Haura: H Lee Moffitt Cancer Centre and Research Institute
Jacob Scott: Cleveland Clinic
Andriy Marusyk: H Lee Moffitt Cancer Centre and Research Institute

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16212-w

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DOI: 10.1038/s41467-020-16212-w

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