Targeting MEK and CDK4/6 in KRAS Mutant Colorectal Cancers Abbreviations: CRC: colorectal cancer; PDX: patient-derived xenograft
نویسندگان
چکیده
Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy that Co-Targets MEK and CDK4/6 Elizabeth K. Ziemke, Joseph S. Dosch, Joel D. Maust, Amrith Shettigar , Ananda Sen, Theodore H. Welling, Karin M. Hardiman, Judith S. Sebolt-Leopold Translational Oncology Program, Department of Radiology, Department of Pharmacology, Department of Family Medicine, Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109
منابع مشابه
Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models
PURPOSE Though the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cy...
متن کاملCancer Therapy: Preclinical Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6
Purpose: The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS) colorectal cancers, where upregulatedCDK4 andhyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. Experimental Design: Initial testing was carried out in the HCT-116 tumor model, which is known to...
متن کاملSensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6.
PURPOSE The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. EXPERIMENTAL DESIGN Initial testing was carried out in the HCT-116 tumor model, which is kn...
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Colorectal cancer (CRC) organoids can be derived from almost all CRC patients and therefore capture the genetic diversity of this disease. We assembled a panel of CRC organoids carrying either wild-type or mutant RAS, as well as normal organoids and tumor organoids with a CRISPR-introduced oncogenic KRAS mutation. Using this panel, we evaluated RAS pathway inhibitors and drug combinations that ...
متن کاملAntitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts
BACKGROUND CRC is a significant cause of cancer mortality, and new therapies are needed for patients with advanced disease. TAK-733 is a highly potent and selective investigational novel MEK allosteric site inhibitor. MATERIALS AND METHODS In a preclinical study of TAK-733, a panel of CRC cell lines were exposed to varying concentrations of the agent for 72 hours followed by a sulforhodamine ...
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