Abstract
Overactivation of the mitogen-activated protein kinase (MAPK) pathway is an important driver of many human cancers. First line, FDA-approved therapies targeting MAPK signalling, which include BRAF and MEK inhibitors, have variable success across cancers, and a significant number of patients quickly develop resistance. In recent years, a number of preclinical studies have reported alternative methods of overcoming resistance, which include promoting apoptosis, modulating autophagy, and targeting mitochondrial metabolism. This review summarizes mechanisms of resistance to approved MAPK-targeted therapies in BRAF-mutated cancers and discusses novel preclinical approaches to overcoming resistance.
Highlights
Constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, through overstimulation of receptors, RAS activation, or uncontrolled kinase activity, drives many human cancers [32]
Recent studies have identified that overexpression of antiapoptotic genes, stimulation of autophagy, adenosine monophosphate protein kinase (AMPK) activation, Table 1: Summary pharmacological interventions for BRAFV600E mutated cancers✝
Preclinical studies have successfully targeted phosphoinositide 3-kinase (PI3K) signalling in combination with BRAF/MEK inhibitors in BRAFV600E-mutated colorectal cancer and melanoma cells [155,156,157]
Summary
Constitutive activation of the MAPK pathway, through overstimulation of receptors, RAS activation, or uncontrolled kinase activity, drives many human cancers [32]. Vemurafenib, a kinase inhibitor, was first used in a phase 1 clinical trial for BRAFV600E-mutated metastatic melanoma in 2010 and was approved for use in 2011 [48, 49]. In 2018, the FDA approved the BRAF/MEK combination encorafenib plus binimetinib for BRAFV600E- and BRAFV600K-mutated metastatic melanoma based on more durable results from a Phase 3 clinical trial [52]. Combining BRAF and MEK inhibitors has improved the average progression-free survival of metastatic melanoma from 5.8 to 9.4 months but many patients still suffer from resistance to combination therapy [50]. Acquired resistance is a cellular alteration in addition to the BRAFV600E mutation that facilitates tumour cells to grow despite BRAF inhibitor (BRAFi) therapy. Reactivation of MAPK signalling is the most common mechanism of acquired resistance to BRAFi therapy across cancer types [57]. MAPK MAPK MAPK MAPK MAPK BH3 mimetic BH3 mimetic BH3 mimetic STAT3 Autophagy Lysosomal autophagy Autophagy DNA replication ER homeostasis UPR# PI3K/AKT/mTOR PI3K/AKT/mTOR P3K/AKT/mTOR P3K/AKT/mTOR PI3K/AKT/mTOR PI3K/AKT/Mitochondria Angiogenesis/inflammation NSAID## NSAID## NSAID## Lipid oxidation Metabolic regulator ETC### Mitochondria Mitochondria CRC/G/M/T CRC/M CRC/M
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