2. Academic Validation
  3. Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations

Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations

  • Cancer Res. 2021 Sep 15;81(18):4685-4695. doi: 10.1158/0008-5472.CAN-21-1153.
Paul Yenerall 1 2,  Rahul K Kollipara 1,  Kimberley Avila 2,  Michael Peyton 2,  Christopher A Eide 3 4,  Daniel Bottomly 3 5,  Shannon K McWeeney 3 5,  Yan Liu 6 7,  Kenneth D Westover 6 7,  Brian J Druker 3 4,  John D Minna 8 9 10 11,  Ralf Kittler 12 9 11
Affiliations

Affiliations

  • 1 McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas.
  • 2 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas.
  • 3 Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
  • 4 Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • 5 Divison of Bioinformatics and Computational Biomedicine, Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science Center, Portland, Oregon.
  • 6 Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas.
  • 7 Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.
  • 8 Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, Texas. ralf.kittler@utsouthwestern.edu john.minna@utsouthwestern.edu.
  • 9 Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas.
  • 10 Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas.
  • 11 Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, Texas.
  • 12 McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas. ralf.kittler@utsouthwestern.edu john.minna@utsouthwestern.edu.
PMID: 34301758 DOI: 10.1158/0008-5472.CAN-21-1153
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-114277
    99.94%, KRAS G12C Inhibitor
    Ras