A Combinatorial Strategy for Targeting BRAF ^V600E-Mutant Cancers with BRAF^V600E Inhibitor (PLX4720) and Tyrosine Kinase Inhibitor (Ponatinib).

ABSTRACT:

Purpose

Most aggressive thyroid cancers are commonly associated with a BRAF ^V600E mutation. Preclinical and clinical data in BRAF ^V600E cancers suggest that combined BRAF and MEK inhibitor treatment results in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAF ^V600E thyroid cancer than in single-agent or BRAF and MEK inhibitors.

Experimental design

The combined drug activity was analyzed to predict any synergistic effect using high-throughput screening (HTS) of active drugs. We performed follow-up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs.

Results

The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion, and migration in BRAF ^V600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720-resistant BRAF ^V600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In an orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth (P < 0.05), decreased the number of metastases (P < 0.05), and increased survival (P < 0.05) compared with monotherapy and vehicle control.

Conclusions

Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF ^V600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.

SUBMITTER: Ghosh C 

PROVIDER: S-EPMC8606228 | biostudies-literature |

REPOSITORIES: biostudies-literature