Targeting parallel bypass signaling to combat adaptive resistance to BRAF inhibition in colorectal cancer

BRAF is a serine/threonine kinase that is downstream of KRAS and immediate upstream of MEK (mitogen-activated protein kinase kinase), and about 8-15% of all colorectal cancer (CRC) patients harbor activating mutations (mostly V600E mutation) of BRAF. BRAF-mutated CRC is a distinct molecular phenotypic and clinical subset that does not respond to chemotherapy, anti-EGFR (Epidermal Growth Factor Receptor) therapy and had the highest mortality. One of the most encouraging developments in oncology has been the success of BRAF inhibitors in BRAF-mutant melanoma: the initial response rate in melanoma is 60-80% [1]. However, BRAF inhibitor monotherapy is ineffective with 0-5% response rate in BRAF-mutant CRCs [2]. Tremendous effort has been put forth to develop effective strategies to overcome BRAF resistance, but thwarting resistance to BRAF inhibitors remains one of the major clinical challenges in therapy against CRC. New perspective can lead to new solution