Abstract

Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti-EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC). Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab. At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment. The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses.

Highlights

  • The introduction of the humanized monoclonal antibodies cetuximab and panitumumab, which target the EGF receptor (EGFR), has widened the therapeutic opportunities for patients with metastatic colorectal cancer

  • The prevalent growth-suppressive effects produced by MEK and phosphoinositide 3-kinase (PI3K)/mTOR inhibition suggest that this strategy may retard disease progression in patients

  • We observed that pharmacologic neutralization of MEK and PI3K/mTOR induced disease stabilization in a high percentage of metastatic colorectal cancer (mCRC) xenografts; this effect was magnified by further addition of cetuximab

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Summary

Introduction

The introduction of the humanized monoclonal antibodies cetuximab and panitumumab, which target the EGF receptor (EGFR), has widened the therapeutic opportunities for patients with metastatic colorectal cancer (mCRC; refs. 1–3). Several phase I studies are currently determining the recommended dose and schedule for RAF, mitogenactivated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK), phosphoinositide 3-kinase (PI3K), AKT or mTOR inhibitors, alone and in combination, in patients with advanced solid tumors These trials are preliminarily analyzing the potential antitumor activity of such compounds as a prelude to their application in genetically defined RAS-mutant cancers. We observed that pharmacologic neutralization of MEK and PI3K/mTOR induced disease stabilization in a high percentage of mCRC xenografts; this effect was magnified by further addition of cetuximab These regimens failed to induce overt tumor shrinkage and the rates of tumor stabilization tended to decrease after prolonged therapy. These results suggest that combined inhibition of MEK and PI3K/mTOR may delay disease progression in patients with RAS mutant mCRCs—a setting for which no effective therapeutic options are currently available—but they issue a word of caution against the occurrence of long-lasting responses

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