Lentiviral-Driven Discovery of Cancer Drug Resistance Mutations.
Cancer Res
; 81(18): 4685-4695, 2021 09 15.
Article
en En
| MEDLINE
| ID: mdl-34301758
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Biomarcadores de Tumor
/
Lentivirus
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Resistencia a Antineoplásicos
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Descubrimiento de Drogas
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Vectores Genéticos
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Mutación
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Neoplasias
Límite:
Humans
Idioma:
En
Revista:
Cancer Res
Año:
2021
Tipo del documento:
Article