Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations.

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 cancer-drug development. SIGNIFICANCE: LentiMutate can evaluate a drug's on-target activity and can nominate resistance mutations before they occur in patients, which could accelerate and refine drug development to increase the survival of patients with cancer.

• Authors: 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
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 18 Pg. 4685-4695 (Sep 15 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 34301758 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Biomarkers, Tumor
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drug Discovery (methods)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Genetic Vectors (genetics)
• Humans
• Lentivirus (genetics)
• Models, Molecular
• Mutation
• Neoplasms (drug therapy, genetics)
• Structure-Activity Relationship