Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells Journal Article
| Authors: | Ali, M.; Lu, M.; Ang, H. X.; Soderquist, R. S.; Eyler, C. E.; Hutchinson, H. M.; Glass, C.; Bassil, C. F.; Lopez, O. M.; Kerr, D. L.; Falcon, C. J.; Yu, H. A.; Hata, A. N.; Blakely, C. M.; McCoach, C. E.; Bivona, T. G.; Wood, K. C. |
| Article Title: | Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells |
| Abstract: | Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells. This DNA damage response, observed in cell lines, mouse xenograft models, and human patients, is driven by a pathway involving the activation of caspases 3 and 7 and the downstream caspase-activated deoxyribonuclease (CAD). CAD is, in turn, activated through caspase-mediated degradation of its endogenous inhibitor, ICAD. In models of EGFR mutant non-small cell lung cancer (NSCLC), tumor cells that survive treatment with small-molecule EGFR-targeted therapies are thus synthetically dependent on ATM, and combined treatment with an ATM kinase inhibitor eradicates these cells in vivo. This led to more penetrant and durable responses in EGFR mutant NSCLC mouse xenograft models, including those derived from both established cell lines and patient tumors. Last, we found that rare patients with EGFR mutant NSCLC harboring co-occurring, loss-of-function mutations in ATM exhibit extended progression-free survival on first generation EGFR inhibitor therapy relative to patients with EGFR mutant NSCLC lacking deleterious ATM mutations. Together, these findings establish a rationale for the mechanism-based integration of ATM inhibitors alongside existing targeted therapies. © 2022 The Authors. |
| Keywords: | controlled study; human tissue; unclassified drug; erlotinib; nonhuman; antineoplastic agent; mouse; animal; animals; mice; animal tissue; dna repair; progression free survival; mitogen activated protein kinase inhibitor; carcinoma, non-small-cell lung; lung neoplasms; animal experiment; animal model; caspase 3; tumor xenograft; lung tumor; oncogene; dna; minimal residual disease; neoplasm, residual; gefitinib; tumor cell; atm protein; dna damage response; double stranded dna break; oncogene k ras; loss of function mutation; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; atr protein; histone h2ax; epidermal growth factor receptor kinase inhibitor; olaparib; braf gene; non small cell lung cancer; molecularly targeted therapy; protein bax; caspase activated deoxyribonuclease; caspase 7; epidermal growth factor receptor gene; quizartinib; n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 difluorophenyl]propanesulfonamide; humans; human; female; article; ceritinib; anaplastic lymphoma kinase gene; osimertinib; pc-9 cell line; azd0156; azd1390; n [3 [[5 chloro 2 [[2 methoxy 4 (4 methyl 1 piperazinyl)phenyl]amino] 4 pyrimidinyl]oxy]phenyl]acrylamide; sch772984; sotorasib; ataxia telangiectasia mutated gene; residual tumor cell |
| Journal Title: | Science Translational Medicine |
| Volume: | 14 |
| Issue: | 638 |
| ISSN: | 1946-6234 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2022-03-30 |
| Start Page: | abc7480 |
| Language: | English |
| DOI: | 10.1126/scitranslmed.abc7480 |
| PUBMED: | 35353542 |
| PROVIDER: | scopus |
| PMCID: | PMC9516479 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2022 -- Source: Scopus |
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