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A Combinatorial Strategy for Targeting BRAF V600E-Mutant Cancers with BRAFV600E Inhibitor (PLX4720) and Tyrosine

Chandrayee Ghosh1, Suresh Kumar2, Yevgeniya Kushchayeva3

  • 1Department of Surgery, Stanford University, Stanford, California.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|January 16, 2020
PubMed
Abstract

Insights

Combining BRAF and multitargeting tyrosine kinase inhibitors (MTKI) shows promise for aggressive thyroid cancer. This combination effectively reduced tumor growth and metastasis in preclinical models, suggesting potential for clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aggressive thyroid cancers frequently harbor the BRAF V600E mutation.
  • While combined BRAF and MEK inhibitor therapy shows initial response, acquired resistance is a significant challenge.
  • Persistent tyrosine kinase (TK) signaling activation via alternative pathways is a key mechanism of acquired resistance.

Purpose of the Study:

  • To investigate the efficacy of combining a BRAF inhibitor with a multitargeting tyrosine kinase inhibitor (MTKI) in BRAF V600E-mutated thyroid cancer.
  • To determine if this combination therapy is more effective than single-agent or BRAF/MEK inhibitor combinations.
  • To explore mechanisms of action and potential to overcome drug resistance.

Main Methods:

  • High-throughput screening (HTS) was employed to identify synergistic drug combinations.
  • In vitro studies utilized BRAF V600E thyroid cancer cell lines to assess proliferation, colony formation, invasion, and migration.
  • In vivo studies were conducted using an orthotopic thyroid cancer mouse model to evaluate tumor growth, metastasis, and survival.

Main Results:

  • The MTKI ponatinib and BRAF inhibitor PLX4720 demonstrated synergistic activity in HTS.
  • Combination therapy significantly inhibited cancer cell proliferation, colony formation, invasion, and migration, while increasing apoptosis.
  • In vivo, the combination therapy markedly reduced tumor growth and metastasis, and improved survival in mice compared to monotherapy.

Conclusions:

  • Combination treatment with ponatinib and PLX4720 exhibits significant synergistic anticancer activity in preclinical BRAF V600E thyroid cancer models.
  • This combination effectively overcomes resistance to PLX4720, resensitizing resistant cells to treatment.
  • The findings support the clinical investigation of this combination therapy for BRAF V600E-mutated thyroid cancers.

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