title: Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer.
abstract: Mutations in theKRASoncogene represent one of the most prevalent genetic alterations in colorectal cancer (CRC), the third leading cause of cancer-related death in the US. In addition to their well-characterized function in driving tumor progression,KRASmutations have been recognized as a critical determinant of the therapeutic response of CRC. Recent studies demonstrate thatKRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor (EGFR) targeting antibodies, including cetuximab and panitumumab. Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment ofKRAS-mutant tumor cells. However, the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear. Despite intensive efforts, directly targeting mutant KRAS has been largely unsuccessful. This review summarizes the recent advances in understanding the biological function ofKRASmutations in determining the therapeutic response of CRC, highlighting several recently developed agents and strategies for targeting mutant KRAS, such as synthetic lethal interactions.
authors: University of Pittsburgh Cancer Institute, Departments of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors: Kyle
authors: K
authors: Knickelbein
authors: University of Pittsburgh Cancer Institute, Departments of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors: Lin
authors: L
authors: Zhang
keywords: EGFR; KRAS; colorectal cancer; synthetic lethality; targeted therapy