Abstract 3865: Multiple cancer types rapidly escape from multiple MAPK inhibitors to generate mutagenesis-prone subpopulations

• Published in: Cancer research (Chicago, Ill.) Vol. 83; no. 7_Supplement; p. 3865
• Main Authors: Hoffman, Timothy E., Yang, Chen, Nangia, Varuna, Ill, Christopher Ryland, Spencer, Sabrina L.
• Format: Journal Article
• Language: English
• Published: 04.04.2023
• DOI: 10.1158/1538-7445.AM2023-3865
• ISSN: 1538-7445

Abstract Many cancers harbor pro-proliferative mutations of the mitogen-activated protein kinase (MAPK) pathway and many targeted inhibitors now exist for clinical use, but drug resistance remains a major issue. We previously showed that BRAF-driven melanoma cells treated with BRAF inhibitors can non-genetically adapt to drug within 3-4 days to escape quiescence and resume slow proliferation. Here we show that this phenomenon is not unique to melanomas treated with BRAF inhibitors but rather is widespread across many clinical MAPK inhibitors and cancer types driven by EGFR, KRAS, and BRAF mutations. In all treatment contexts examined, a subset of cells can escape drug-induced quiescence within four days to resume proliferation. These escapee cells broadly experience aberrant DNA replication, accumulate DNA lesions, spend longer in G2-M cell cycle phases, and mount an ATR-dependent stress response. We further identify the Fanconi anemia (FA) DNA repair pathway as critical for successful mitotic completion in escapees. Long-term cultures, patient samples, and clinical data demonstrate a broad dependency on ATR- and FA-mediated stress tolerance. Together, these results highlight the pervasiveness with which MAPK-mutant cancers are able to rapidly escape drug and the importance of suppressing early stress tolerance pathways to potentially achieve more durable clinical responses to targeted MAPK pathway inhibitors. Citation Format: Timothy E. Hoffman, Chen Yang, Varuna Nangia, Christopher Ryland Ill, Sabrina L. Spencer. Multiple cancer types rapidly escape from multiple MAPK inhibitors to generate mutagenesis-prone subpopulations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3865.