AKT is critically involved in the antagonism of BRAF inhibitor sorafenib against dabrafenib in colorectal cancer cells harboring both wild-type and mutant (V600E) BRAF genes

BRAF, one of the key factors in mitogen-activated protein kinase (MAPK) signaling pathway, plays an important role in cell functions including growth and proliferation. Inhibition of BRAF represents a promising antitumor strategy. Dabrafenib, a type I inhibitor of BRAF interrupting RAF/MEK interaction, has been approved by FDA as a single agent or combined with MEK inhibitor trametinib for the treatment of patients with BRAF V600E mutation-positive advanced melanoma. In the present study, we investigated the feasibility of combined treatment with dabrafenib and sorafenib, type I and type II BRAF inhibitor respectively, on colorectal cancer cells with BRAF V600E mutation. Unexpectedly, sorafenib significantly antagonized the inhibition effect of dabrafenib on the proliferation of colorectal cancer HT-29 and Colo205 cells. The antagonism relied on co-existence of wild-type and mutant (V600E) BRAF, for no antagonism was observed in tumor cells expressing homozygous wild-type or mutant (V600E) BRAF. BRAF, but not CRAF, was required for this antagonism. Moreover, we found that sorafenib reversed dabrafenib inhibition of AKT in HT-29 cells, and phosphatidylinositol-3-kinase (PI3K) inhibitor GDC0941 significantly restored this antagonistic effect when combined with dabrafenib and sorafenib, indicating that AKT is critically involved in this antagonism. Collectively, we found that significant antagonism was observed when dabrafenib was combined with sorafenib in colorectal cancer cells harboring heterozygous genotype of BRAF and AKT is critically involved in this antagonism. We suggest that BRAF inhibitor dabrafenib and sorafenib should not be combined in clinic. - Highlights: • Sorafenib antagonizes dabrafenib in cancer cells with heterozygous BRAF V600E. • Sorafenib reverses dabrafenib inhibition of AKT. • AKT is critically involved in this antagonism of sorafenib against dabrafenib. • PI3K inhibitor restores the antagonism of sorafenib against dabrafenib.