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Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6

Elizabeth K Ziemke¹, Joseph S Dosch¹, Joel D Maust²

¹Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research

|September 16, 2015

Abstract

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 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.

Results:

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.

Conclusions:

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.

Insights

Cotargeting MEK and CDK4/6 with trametinib and palbociclib showed significant efficacy in KRAS-mutant colorectal cancers. This combination therapy was well-tolerated and demonstrated promising preclinical antitumor activity in patient-derived models.

Area of Science:

Oncology
Molecular Biology
Cancer Therapeutics

Background:

Colorectal cancers with KRAS mutations often exhibit upregulated CDK4 and hyperphosphorylated retinoblastoma (RB).
Rational combination treatments are needed for effective cancer therapy.

Purpose of the Study:

To investigate the efficacy of cotargeting MEK and CDK4/6 in KRAS-mutant (KRAS(mt)) colorectal cancers.
To evaluate the combination of trametinib (MEK inhibitor) and palbociclib (CDK4/6 inhibitor).

Main Methods:

In vitro synergy testing using HCT-116 cells (KRAS-mutant).
In vivo efficacy studies in patient-derived colorectal xenograft (PDX) models with diverse genomic profiles.
Evaluation of tolerance, efficacy, and pharmacodynamic modulation with single-agent and combination treatments.

Main Results:

Synergistic antitumor activity observed in vitro and in vivo with the trametinib and palbociclib combination.
The combination was well tolerated and achieved objective responses in all tested KRAS(mt) PDX models.
Tumor stasis was noted in KRAS/BRAF wild-type and BRAF(mt) models.

Conclusions:

Combination therapy with trametinib and palbociclib is well tolerated and highly effective in KRAS-mutant colorectal cancer PDX models.
The promising preclinical data support clinical evaluation for metastatic colorectal cancer treatment.

Read full analysis

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