Reference Detail

Ref Type Journal Article
PMID (26369631)
Authors Ziemke EK, Dosch JS, Maust JD, Shettigar A, Sen A, Welling TH, Hardiman KM, Sebolt-Leopold JS
Title Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 2
Date 2016 Jan 15
URL
Abstract Text 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.Initial testing was carried out in the HCT-116 tumor model, which is known to harbor a KRAS mutation. Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models, genomically diverse with respect to KRAS, BRAF, and PIK3CA mutational status. Tolerance, efficacy, and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration.Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib. Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment. Testing of colorectal patient-derived xenograft (PDX) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS(mt) models tested. Stasis was observed in a KRAS/BRAF wild-type and a BRAF(mt) model.Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested. Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E KRAS wild-type colorectal cancer no benefit Palbociclib + Trametinib Preclinical - Pdx Actionable In a preclinical study, Mekinist (trametinib) and Ibrance (palbociclib) combination treatment did not result in enhanced antitumor activity compared to Ibrance (palbociclib) alone in PDX models of KRAS wild-type colorectal cancer harboring BRAF V600E (PMID: 26369631). 26369631
KRAS mutant colorectal cancer sensitive Palbociclib + Trametinib Preclinical - Pdx Actionable In a preclinical study, Mekinist (trametinib) and Ibrance (palbociclib) combination treatment resulted in objective response in PDX models of colorectal cancer cells harboring KRAS mutations (PMID: 26369631). 26369631
KRAS G13D colorectal cancer sensitive Palbociclib + Trametinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Mekinist (trametinib) and Ibrance (palbociclib) synergistically inhibited growth of colorectal cancer cells harboring KRAS G13D in culture and resulted in partial tumor regression in patient-derived xenograft models (PMID: 26369631). 26369631