Inhibition of MEK and PI3K/mTOR Suppresses Tumor Growth but Does Not Cause Tumor Regression in Patient-Derived Xenografts of RAS-Mutant Colorectal Carcinomas

Abstract

Purpose: 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). Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 18(9); 2515–25. ©2012 AACR.

DEPTOR Expression Negatively Correlates with mTORC1 Activity and Tumor Progression in Colorectal Cancer

“…It was recently demonstrated that mTOR inhibitors have anti-tumor effects (Bijnsdorp et al, 2011;Finn., 2012;Migliardi et al, 2012). However, our study failed to determine the relationship between the expression of P-S6 (S235/236), DEPTOR and overall survival in CRC.…”

Molecular Profiling of Patients with Colorectal Cancer and Matched Targeted Therapy in Phase I Clinical Trials

“…In preclinical models, inhibiting the PI3K pathway showed synergy with cytotoxic agents, enhancing its efficacy by potentiating apoptosis (41). In addition, dual inhibition of the RAF/MEK and PI3K/AKT/mTOR pathways seems to be required for complete abrogation of downstream effectors in RASmutant tumors (19)(20)(21). PIK3CA and PTEN mutations strongly reduce the sensitivity of RAS-mutant cells to MEK inhibitors (42).…”

“…It is also important to highlight the fact that the use of full doses of both targeted agents was rarely achieved because of overlapping toxicities. Interestingly, in patient-derived metastatic colorectal cancer xenografts exhibiting KRAS and BRAF mutations, concomitant inhibition of PI3K/ mTOR and MEK pathway activity proved to be more effective than single pathway inhibition, although the best response was limited to tumor growth arrest rather than overt tumor regression (21). This observation is potentially important for further drug development in RAS/RAFmutant colorectal cancers.…”

“…Their study designs are based on preclinical and early clinical response data showing the potential predictive value of specific molecular aberrations. Examples include PIK3CA-activating mutations and loss of PTEN expression and benefit with PI3K pathway inhibitors (15,16), synergistic antitumor activity with combination blockade of mTOR and IGF1R signaling (17,18), RAS/RAF mutations and response to PI3K pathway inhibitors plus MEK inhibitors (19)(20)(21), BRAF mutations linked to antitumor activity of selective BRAF inhibitors (22,23), and MET hyperactivation and benefit with MET/ HGF targeting agents (24,25).…”

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

“…For instance, KRAS mutations are frequent in human cancer and are generally considered to be "actionable," as the oncogene addiction model predicts that treatment of such patients with a MEK inhibitor (a kinase downstream of KRAS) would deliver clinical benefit. However, in both preclinical models of KRAS-mutant cancers and in early clinical studies, responses of KRAS-mutant tumors to MEK inhibitors have proven to be modest (14)(15)(16). It will therefore be important to define more unambiguously what the term "actionable" means.…”