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APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Hideko Isozaki, Ammal Abbasi, Naveed Nikpour, Adam Langenbucher, Wenjia Su, Marcello Stanzione, Heidie Frisco Cabanos, Faria M. Siddiqui, Nicole Phan, Pégah Jalili, Sunwoo Oh, Daria Timonina, Samantha Bilton, Maria Gomez-Caraballo, Hannah L. Archibald, Varuna Nangia, Kristin Dionne, Amanda Riley, Matthew Lawlor, Mandeep Kaur Banwait, Rosemary G. Cobb, Lee Zou, Nicholas J. Dyson, Christopher J. Ott, Cyril Benes, Gad Getz, Chang S. Chan, Alice T. Shaw, Jessica J. Lin, Lecia V. Sequist, Zofia Piotrowska, Jeffrey A. Engelman, Jake June-Koo Lee, Yosef Maruvka, Rémi Buisson, Michael S. Lawrence, Aaron N. Hata
doi: https://doi.org/10.1101/2021.01.20.426852
Hideko Isozaki
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Ammal Abbasi
1Massachusetts General Hospital Cancer Center, Boston, MA
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Naveed Nikpour
1Massachusetts General Hospital Cancer Center, Boston, MA
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Adam Langenbucher
1Massachusetts General Hospital Cancer Center, Boston, MA
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Wenjia Su
1Massachusetts General Hospital Cancer Center, Boston, MA
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Marcello Stanzione
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Heidie Frisco Cabanos
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Faria M. Siddiqui
1Massachusetts General Hospital Cancer Center, Boston, MA
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Nicole Phan
1Massachusetts General Hospital Cancer Center, Boston, MA
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Pégah Jalili
8Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA
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Sunwoo Oh
8Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA
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Daria Timonina
1Massachusetts General Hospital Cancer Center, Boston, MA
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Samantha Bilton
1Massachusetts General Hospital Cancer Center, Boston, MA
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Maria Gomez-Caraballo
1Massachusetts General Hospital Cancer Center, Boston, MA
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Hannah L. Archibald
1Massachusetts General Hospital Cancer Center, Boston, MA
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Varuna Nangia
1Massachusetts General Hospital Cancer Center, Boston, MA
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Kristin Dionne
1Massachusetts General Hospital Cancer Center, Boston, MA
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Amanda Riley
1Massachusetts General Hospital Cancer Center, Boston, MA
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Matthew Lawlor
1Massachusetts General Hospital Cancer Center, Boston, MA
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Mandeep Kaur Banwait
1Massachusetts General Hospital Cancer Center, Boston, MA
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Rosemary G. Cobb
1Massachusetts General Hospital Cancer Center, Boston, MA
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Lee Zou
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Nicholas J. Dyson
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Christopher J. Ott
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
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Cyril Benes
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Gad Getz
1Massachusetts General Hospital Cancer Center, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
4Department of Pathology, Massachusetts General Hospital, Boston, MA
5Department of Pathology, Harvard Medical School, Boston, MA
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Chang S. Chan
6Department of Medicine, Rutgers Robert Wood Johnson Medical School and Center for Systems and Computational Biology, Rutgers Cancer Institute, New Brunswick, NJ
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Alice T. Shaw
1Massachusetts General Hospital Cancer Center, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
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Jessica J. Lin
1Massachusetts General Hospital Cancer Center, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
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Lecia V. Sequist
1Massachusetts General Hospital Cancer Center, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
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Zofia Piotrowska
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Jeffrey A. Engelman
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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Jake June-Koo Lee
2Department of Medicine, Harvard Medical School, Boston, MA
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Yosef Maruvka
7Faculty of Biotechnology and Food engineering, Technion, Israel
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Rémi Buisson
8Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine, Irvine, CA
9Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California Irvine, Irvine, California, USA
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Michael S. Lawrence
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
3Broad Institute of MIT and Harvard, Cambridge, MA
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  • For correspondence: ahata@mgh.harvard.edu lawrence@broadinstitute.org
Aaron N. Hata
1Massachusetts General Hospital Cancer Center, Boston, MA
2Department of Medicine, Harvard Medical School, Boston, MA
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  • For correspondence: ahata@mgh.harvard.edu lawrence@broadinstitute.org
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Abstract

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

Competing Interest Statement

The authors declare competing financial interests: A.N.H. has received grants/research support from Novartis, Amgen, Pfizer, Eli Lilly, Roche/Genentech, Eli Lilly, Relay Therapeutics and Blueprint Medicines. L.V.S. has served as a compensated consultant for Genentech, AstraZeneca and Janssen, and has has received institutional research support from BI, AZ, Novartis, Genentech, LOXO and Blueprint Medicines. Z.P. has served as a compensated consultant or received honoraria from C4 Therapuetics, Blueprint Medicines, Jazz Pharmaceuticals, Janssen, Medtronic, Eli Lilly, InCyte AstraZeneca, Genentech, Spectrum, Ariad/Takeda, Novartis, AbbVie and Guardant Health, and receives institutional research funding from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro and Cullinan Oncology. J.J.L. has served as a compensated consultant or received honorarium from Chugai Pharma, Boehringer-Ingelheim, Pfizer, C4 Therapeutics, Nuvalent, Turning Point Therapeutics, Blueprint Medicines, and Genentech; received institutional research funds from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Roche/Genentech, Pfizer, and Novartis; and received travel support from Pfizer. C.B., A.T.S. and J.A.E are currently are currently employees of Novartis, Inc. (their contributions to the manuscript occurred while they were employees of Massachusetts General Hospital).  

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APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer
Hideko Isozaki, Ammal Abbasi, Naveed Nikpour, Adam Langenbucher, Wenjia Su, Marcello Stanzione, Heidie Frisco Cabanos, Faria M. Siddiqui, Nicole Phan, Pégah Jalili, Sunwoo Oh, Daria Timonina, Samantha Bilton, Maria Gomez-Caraballo, Hannah L. Archibald, Varuna Nangia, Kristin Dionne, Amanda Riley, Matthew Lawlor, Mandeep Kaur Banwait, Rosemary G. Cobb, Lee Zou, Nicholas J. Dyson, Christopher J. Ott, Cyril Benes, Gad Getz, Chang S. Chan, Alice T. Shaw, Jessica J. Lin, Lecia V. Sequist, Zofia Piotrowska, Jeffrey A. Engelman, Jake June-Koo Lee, Yosef Maruvka, Rémi Buisson, Michael S. Lawrence, Aaron N. Hata
bioRxiv 2021.01.20.426852; doi: https://doi.org/10.1101/2021.01.20.426852
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APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer
Hideko Isozaki, Ammal Abbasi, Naveed Nikpour, Adam Langenbucher, Wenjia Su, Marcello Stanzione, Heidie Frisco Cabanos, Faria M. Siddiqui, Nicole Phan, Pégah Jalili, Sunwoo Oh, Daria Timonina, Samantha Bilton, Maria Gomez-Caraballo, Hannah L. Archibald, Varuna Nangia, Kristin Dionne, Amanda Riley, Matthew Lawlor, Mandeep Kaur Banwait, Rosemary G. Cobb, Lee Zou, Nicholas J. Dyson, Christopher J. Ott, Cyril Benes, Gad Getz, Chang S. Chan, Alice T. Shaw, Jessica J. Lin, Lecia V. Sequist, Zofia Piotrowska, Jeffrey A. Engelman, Jake June-Koo Lee, Yosef Maruvka, Rémi Buisson, Michael S. Lawrence, Aaron N. Hata
bioRxiv 2021.01.20.426852; doi: https://doi.org/10.1101/2021.01.20.426852

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