Multi-kinase modulation for colon cancer therapy

Abstract

It is now well recognized that in the vast majority of tumor types, for the approach of “kinase inhibition” to exhibit a significant effect, whether the data are from an in vitro assay, an animal model or the clinic, requires that multiple complementary kinases be simultaneously inhibited. This combined inhibition is not only kill the tumor cell but also to suppress and kill tumor cells that seek to avoid the initial induction of death processes via compensatory survival signaling mechanisms.¹ Even within the broad brush definition of carcinomas from a particular organ, there are a range of mutations which present that will profoundly or sometimes more subtly change the paradigm for therapeutic intervention using multiple kinase inhibitor combinations. For example, in colorectal cancer the K-RAS oncogene frequently has an activating mutation implying that inhibition of RAF-MEK1/2-ERK1/2 signaling, but not an initiating receptor upstream of K-RAS, could have a therapeutic effect; however, some colon cell lines with the K-RAS mutation are still noted to be sensitive to upstream ERBB1 inhibitors.^2,3 Also, compensatory feedback survival signaling loops can cause, after inhibition of a mutant active intracellular oncogenic kinase such as B-RAF V600E, a survival activation of growth factor receptors in a tumor cell.⁴ The clinical studies in the manuscript by Al-Marrawi et al. describe the rational combination of signaling inhibitors in a colon cancer patient whose tumor cells express a mutant active B-RAF V600E protein that signals into the MEK1/2-ERK1/2 pathway downstream of K-RAS; this is a particularly aggressive form of colon cancer for which few rational therapeutic interventions have been available until recent times.^5,6

Keywords: :

• BAY43-9006
• RAF inhibitor
• cetuximab
• colorectal cancer therapy
• combined therapy
• sorafenib
• sorafenib and cetuximab

This article refers to:

Off-label use of cetuximab plus sorafenib and panitumumab plus regorafenib to personalize therapy for a patient with V600E BRAF-mutant metastatic colon cancer

10.4161/cbt.26176

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

PD is funded by R01 DK52825.