Lentiviral-driven discovery of cancer drug resistance mutations

Paul Yenerall, Rahul K. Kollipara, Kimberley Avila, Michael Peyton, Christopher A. Eide, Daniel Bottomly, Shannon K. McWeeney, Yan Liu, Kenneth D. Westover, Brian J. Druker, John D. Minna, Ralf Kittler

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Identifying resistance mutations in a drug target provides crucial information. Lentiviral transduction creates multiple types of mutations due to the error-prone nature of the HIV-1 reverse transcriptase (RT). Here we optimized and leveraged this property to identify drug resistance mutations, developing a technique we term LentiMutate. This technique was validated by identifying clinically relevant EGFR resistance mutations, then applied to two additional clinical anticancer drugs: Imatinib, a BCR-ABL inhibitor, and AMG 510, a KRAS G12C inhibitor. Novel deletions in BCR-ABL1 conferred resistance to imatinib. In KRAS-G12C or wild-type KRAS, point mutations in the AMG 510 binding pocket or oncogenic non- G12C mutations conferred resistance to AMG 510. LentiMutate should prove highly valuable for clinical and preclinical cancerdrug development.

Original languageEnglish (US)
Pages (from-to)4685-4695
Number of pages11
JournalCancer Research
Volume81
Issue number18
DOIs
StatePublished - Sep 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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