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Ref Type Journal Article
PMID (31937621)
Authors Ghosh C, Kumar S, Kushchayeva Y, Gaskins K, Boufraqech M, Wei D, Gara SK, Zhang L, Zhang YQ, Shen M, Mukherjee S, Kebebew E
Title A Combinatorial Strategy for Targeting BRAFV600E-Mutant Cancers with BRAFV600E Inhibitor (PLX4720) and Tyrosine Kinase Inhibitor (Ponatinib).
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 26
Issue 8
Date 2020 Apr 15
URL
Abstract Text Most aggressive thyroid cancers are commonly associated with a BRAFV600E mutation. Preclinical and clinical data in BRAFV600E 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 BRAFV600E thyroid cancer than in single-agent or BRAF and MEK inhibitors.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.The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion, and migration in BRAFV600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720-resistant BRAFV600E 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.Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAFV600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E thyroid gland cancer sensitive PLX4720 + Ponatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Iclusig (ponatinib) and PLX4720 treatment demonstrated synergy, and inhibited Erk, Mek, and c-jun phosphorylation, reduced cell proliferation, colony formation, and migration, and induced apoptosis in thyroid cancer cells harboring BRAF V600E and in PLX4720-resistant cells harboring BRAF V600E in culture, and inhibited tumor growth, reduced lung and liver metastases, and increased survival in cell line xenograft models (PMID: 31937621). 31937621
BRAF V600E thyroid gland cancer sensitive Ponatinib + Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) and Zelboraf (vemurafenib) treatment synergistically inhibited proliferation of thyroid cancer cells harboring BRAF V600E in culture (PMID: 31937621). 31937621