The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer

Abstract

Purpose: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/ mTOR and RAF/MEK/ERK pathways.Experimental Design: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program.Results: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P ¼ 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n ¼ 7; melanoma, n ¼ 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%.Conclusions: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth. Clin Cancer Res; 18(8); 2316-25. Ó2012 AACR.

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

“…The clinical impact of such a parallel pathway blockade remains unclear, but none of the 11 patients treated with PI3K pathway inhibitors plus MEK inhibitors in our series had benefit in terms of response or disease stabilization. A recently published large data set reported similarly disappointing results, with no partial responses or disease stabilizations for more than 16 weeks in 16 patients with metastatic colorectal cancers treated using the same approach (43).…”

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

“…It was reported that p-EGFR level was much higher in 4T1 tumors than in cell cultures, suggesting potential crosstalk with exogenous growth factors and cytokines in the in vivo tumor environment and that combinatorial targeting of FGFR and EGFR might be advantageous (38,82). Although combination therapy with selective inhibitors is possible when available, rationally designed dual and multitargeted inhibitors have the potential advantage of possessing the desired polypharmacology engineered into a single compound, thereby avoiding potential drug-drug interactions that can arise with combination treatment (83). Dual covalent inhibitors of EGFR and VEGFR have been designed previously, but these compounds possessed two electrophilic groups.…”

“Combo” nanomedicine: Co-delivery of multi-modal therapeutics for efficient, targeted, and safe cancer therapy

“…The study also suggested that the combination may be synergistic in different genomic backgrounds and can block the multiple cyclinD1-and CDK4-activating mechanisms for inhibited growth and proliferation of PI3Ki resistant cells. Simultaneous co-inhibition of RAS/RAF/MAPK and PI3K/AKT/mTOR pathways has emerged as a popular scheme for combination therapy [108][109][110]. Targeting these two pathways may be particularly effective in cancers attributed to mutations in PI3K and either KRAS or BRAF [108].…”

“…Simultaneous co-inhibition of RAS/RAF/MAPK and PI3K/AKT/mTOR pathways has emerged as a popular scheme for combination therapy [108][109][110]. Targeting these two pathways may be particularly effective in cancers attributed to mutations in PI3K and either KRAS or BRAF [108]. In ovarian clear cell carcinoma, inhibition of a downstream target of mTOR and HIF-1 activated the RAS pathway via MEK phosphorylation, and combination therapy using inhibitors of MEK and mTOR simultaneously synergistically eradicated HIF-1α-silenced cells [111].…”