PI3K and MEK inhibitor combinations: examining the evidence in selected tumor types

Abstract

The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Molecular alterations in these pathways are implicated in tumorigenesis and resistance to anticancer therapies. The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are known to interact with each other at several nodes, and mounting evidence suggests that dual blockade of both pathways may be required to achieve anticancer effects in certain contexts. This may include tumor types with a high frequency of RAS/RAF/MEK/ERK pathway activation, or situations in which dual pathway strategies may be required to overcome resistance to current targeted therapies. Several clinical studies are currently evaluating the combination of PI3K and MEK inhibitors in a variety of different cancers with certain types of molecular alterations. This review will summarize existing knowledge of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, the cross-talk between them, and the current generation of PI3K and MEK inhibitors that target them. The preclinical rationale for dual pathway inhibition will be discussed within the context of the major tumor types currently being explored in ongoing clinical trials, namely malignant melanoma with BRAF or NRAS mutations, and colorectal, ovarian, pancreatic, and basal-like breast cancers. The emerging clinical profile of PI3K and MEK inhibitor combinations, as reported in Phase I trials, will also be discussed.

Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab

“…The combined treatment with cetuximab plus regorafenib shows a synergistic antitumor effect both in vitro and in vivo, providing the rational for the clinical development of this combination. These results are consistent with previous reports, which showed that combined inhibition of different growth controlling pathways might potentially exhibit a better therapeutic efficacy compared with inhibition of a single pathway (38)(39)(40). In this respect, regorafenib inhibits multiple cell membrane tyrosine kinase receptors that are involved in key processes of cancer development and progression, including angiogenesis (17).…”

MicroRNAs 206 and 21 Cooperate To Promote RAS–Extracellular Signal-Regulated Kinase Signaling by Suppressing the Translation of RASA1 and SPRED1

“…genetic changes in these receptors or the mutational activation of RAS or RAF are rare, these tumors often harbor other genetic alterations that promote RAS-ERK pathway activity (26)(27)(28)(29)(30)(31). Supporting the importance of this signaling, TNBC cells are particularly sensitive to drugs such as MEK or PI 3-kinase inhibitors, and combination therapies have been analyzed in clinical trials (23,24,78,79).…”

Colorectal cancer carcinogenesis: a review of mechanisms

“…Loss-of-function mutations in PTEN, which is a tumor suppressor and an antagonist of the PI3K/AKT pathway, induce AKT-regulated metastasis in CRCs 54 . The MEK/ERK and PI3K/AKT pathways often converge to activate a cap-dependent translation through survivin knockdown, which can inhibit metastasis 55 . Therefore, targeting both pathways together is more clinically effective 56 .…”