TY - JOUR
T1 - Lentiviral-driven discovery of cancer drug resistance mutations
AU - Yenerall, Paul
AU - Kollipara, Rahul K.
AU - Avila, Kimberley
AU - Peyton, Michael
AU - Eide, Christopher A.
AU - Bottomly, Daniel
AU - McWeeney, Shannon K.
AU - Liu, Yan
AU - Westover, Kenneth D.
AU - Druker, Brian J.
AU - Minna, John D.
AU - Kittler, Ralf
N1 - Funding Information:
The authors thank the UT Southwestern (UTSW) McDermott Sequencing Core for their technical assistance and Chelsea Burroughs for generating graphics. This study was supported by funding from the Simmons Comprehensive Cancer Center at UTSW (developmental funds to R. Kittler from P30CA142543), CPRIT (RP120732-P3 to R. Kittler, RP160652 to J.D. Minna, RP170373 to K.D. Westover), the NIH (NCI SPORE in lung cancer 5P50CA070907 to J.D. Minna, R01CA200787 to R. Kittler, R01CA244341 to K.D. Westover, and R01CA065823 to B.J. Druker), the Margot Johnson Foundation to J.D. Minna, and the Howard Hughes Medical Institute to B.J. Druker. R. Kittler is a John L. Roach Scholar in Biomedical Research and a CPRIT Scholar in Cancer Research.
Funding Information:
P. Yenerall reports a patent for "Methods and Compositions for Mutagenesis Screening in Mammalian Cells" application # 63158723 pending. C.A. Eide reports grants from NIH/NCI during the conduct of the study. S.K. McWeeney reports grants from NIH during the conduct of the study. K.D. Westover reports grants from NIH, US Department of Defense; grants from CPRIT during the conduct of the study; grants from Revolution Medicines outside the submitted work; and is on the scientific advisory board of Vibliome Therapeutics. B.J. Druker reports grants from NIH NCI R01 during the conduct of the study; personal fees from Aileron Therapeutics, Therapy Architects, LLC (Parent company of ALLCRON Pharma Inc.), Amgen, Aptose Biosciences, Iterion Therapeutics, Blueprint Medicines, Burroughs Wellcome Fund, Cepheid, GRAIL, Nemucore Medical Innovations, Recludix Pharma, VB Therapeutics, Vincerx Pharma, Vivid Biosciences, Gilead Sciences, ICON (formerly Molecular MD), Monojul personal fees and other support from EnlIven Therapeutics, Novartis; other support from Beat AML LLC, CureOne, Bristol-Myers Squibb; and other support from Pfizer outside the submitted work; in addition, B.J. Druker has a patent for Treatment of Gastrointestinal Stromal Tumors issued, licensed, and with royalties paid from Novartis. J.D. Minna reports grants from National Institutes of Health, grants from Cancer Prevention and Research Institute of Texas, and grants from Margot Johnson Foundation during the conduct of the study; personal fees from National Institutes of Health and personal fees from University of Texas Southwestern Medical Center outside the submitted work; in addition, J.D. Minna has a patent for LentiMutate pending. R. Kittler reports grants from NIH-NCI and grants from CPRIT during the conduct of the study; in addition, R. Kittler has a patent for Provisional US Patent application pending. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 The Authors.
PY - 2021/9/15
Y1 - 2021/9/15
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85115034101&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-21-1153
DO - 10.1158/0008-5472.CAN-21-1153
M3 - Article
C2 - 34301758
AN - SCOPUS:85115034101
SN - 0008-5472
VL - 81
SP - 4685
EP - 4695
JO - Cancer research
JF - Cancer research
IS - 18
ER -