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Figure S1 from Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations

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posted on 2023-03-30, 14:02 authored by 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

Expression of RUVBL1 variants identified by LentiMutate confer resistance to compound B Individual cDNAs were expressed in the H1993 (left) or H2009 (right) cell lines under a doxycycline-inducible promoter. Values shown are averages of two biological replicates {plus minus} the standard deviation.

Funding

Cancer Prevention and Research Institute of Texas (CPRIT)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Howard Hughes Medical Institute (HHMI)

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ARTICLE 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. 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.

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    Cancer Research

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    cancer

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