Molecular Pathways: Adaptive Kinome Reprogramming in Response to Targeted Inhibition of the BRAF–MEK–ERK Pathway in Cancer

Abstract

The central role of the BRAF-MEK-ERK pathway in controlling cell fate has made this pathway a primary target for deregulated activation in cancer. BRaf is activated by Ras proteins allowing Ras oncogenes to constitutively activate the pathway. Activating BRaf mutations are also frequent in several cancers, being the most common oncogenic mutation in thyroid carcinoma and melanoma. There are currently two inhibitors, vemurafenib and dabrafenib, approved for treatment of malignant melanoma having activating BRaf mutations. Concurrent administration of BRAF inhibitor and MEK inhibitor (trametinib) is significantly more active in patients with BRAF mutant melanoma than either single agent alone, but progression to resistance ultimately occurs by different mechanisms that increase the activation of ERK. Such adaptive changes in tumor cell signaling networks allows bypass of targeted oncoprotein inhibition. This is true with targeted inhibitors for BRaf and MEK as well as specific inhibitors for AKT, mTOR and many receptor tyrosine kinases such as EGFR and HER2. It is this adaptive response to targeted kinase inhibitors that contributes to the failure of single agent kinase inhibitors to have durable responses. This failure is seen in virtually all cancers treated with single agent kinase inhibitors, most of which are not as dependent on a single signaling pathway such as BRaf-MEK-ERK in melanoma. Thus, understanding the breadth of adaptive reprogramming responses to specific targeted kinase inhibition will be critical to develop appropriate combination therapies for durable clinical responses.

mTOR activity and its prognostic significance in human colorectal carcinoma depending on C1 and C2 complex-related protein expression

“…mTOR activity—especially related to the mTORC2 complex—has also emerged as a driving force behind intrinsic or acquired resistance to targeted drugs used in clinical practice such as HER2 or BRAF inhibitors. Several clinical trials have addressed this issue, and it would be interesting to investigate mTOR activity and Rictor expression in situ in these cases as well 37 38. Rictor overexpression could also be interesting because Rictor has also been reported in focal adhesion complexes where it may enhance cellular survival and metastatic spread of tumour cells in an mTOR-independent manner 39…”

Antiproliferative effects of formononetin on human colorectal cancer via suppressing cell growth in vitro and in vivo

“…Dysregulation of the ERK expression commonly occurs in diseased cells, such as cancers, in which phosphorylation of ERKs causes activation of the specific kinase activity that controls cell survival or death [27,28]. Therefore, inactivating intracellular ERK pathway is a therapeutic way to manage the proliferation of cancer cells.…”

The butterfly effect in cancer: A single base mutation can remodel the cell

“…Our work is in substantial agreement with that comparison; the two studies are mutually supportive and complementary. Support for a systematic cellular connectivity also comes from investigations on protein kinases (21)(22)(23). Molecular mechanisms that could induce the multiple changes identified in MCF-10A cells would include, besides canonical signaling, differential levels of micro-RNAs, long noncoding RNAs, and epigenetic changes.…”