Pharmaceutical Reactivation of Attenuated Apoptotic Pathways Leads to Elimination of Osimertinib Drug-Tolerant Cells.

ABSTRACT: Osimertinib is an EGFR tyrosine kinase inhibitor (TKI) with proven clinical efficacy; however, acquired resistance presents an obstacle to curing EGFR-driven disease. Recent studies have shown that drug-tolerant persister cells (DTP) have a distinct transcriptional profile that may confer specific vulnerabilities. By definition these cells avoid apoptosis, yet little is known about how their survival is regulated. We found that paradoxically, the proapoptotic gene BIM was upregulated in osimertinib DTPs, and cotreatment with BH3 mimetics could trigger DTP cell death. Furthermore, cIAP proteins, antiapoptotic members of the extrinsic pathway, were significantly elevated in DTPs. cIAP antagonists could block DTP formation as an up-front combination, and could eliminate preformed DTPs.

SUBMITTER: Martin MJ 

PROVIDER: S-EPMC10035388 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature