The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells.

Autor: Criscione SW; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA. Steven.Criscione@astrazeneca.com., Martin MJ; Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK., Oien DB; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Gorthi A; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA.; Department of Cell Systems & Anatomy, Greehey Children's Cancer Research Institute, University of Texas at Health San Antonio, San Antonio, TX, USA., Miragaia RJ; Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK., Zhang J; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Chen H; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Karl DL; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Mendler K; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Markovets A; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Gagrica S; Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK., Delpuech O; Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK., Dry JR; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Grondine M; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Hattersley MM; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Urosevic J; Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK., Floc'h N; Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK., Drew L; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA., Yao Y; Research and Early Development, Oncology R&D, AstraZeneca, Boston, MA, USA. yiyao1147@gmail.com., Smith PD; Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK. Paul.D.Smith@astrazeneca.com.
Jazyk: angličtina
Zdroj: NPJ precision oncology [NPJ Precis Oncol] 2022 Dec 27; Vol. 6 (1), pp. 95. Date of Electronic Publication: 2022 Dec 27.
DOI: 10.1038/s41698-022-00337-w
Abstrakt: Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.
(© 2022. The Author(s).)
Databáze: MEDLINE
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