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

被引：14

作者：

Ghosh, Chandrayee ^{[1
]}

Kumar, Suresh ^{[2
]}

Kushchayeva, Yevgeniya ^{[3
]}

Gaskins, Kelli ^{[4
]}

Boufraqech, Myriem ^{[4
]}

Wei, Darmood ^{[4
]}

Gara, Sudheer Kumar ^{[4
]}

Zhang, Lisa ^{[5
]}

Zhang, Ya-qin ^{[6
]}

Shen, Min ^{[6
]}

Mukherjee, Sanjit ^{[7
]}

Kebebew, Electron ^{[1
]}

机构：

[1] Stanford Univ, Dept Surg, Stanford, CA 94305 USA

[2] NIA, Lab Genet & Genom, Bethesda, MD 20892 USA

[3] Natl Inst Digest & Kidney Dis, NIH, Bethesda, MD USA

[4] NCI, NIH, Bethesda, MD 20892 USA

[5] Natl Inst Child Hlth & Dev, NIH, Bethesda, MD USA

[6] NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA

[7] NCI, Genet Branch, Bethesda, MD 20892 USA

来源：

CLINICAL CANCER RESEARCH | 2020年 / 26卷 / 08期

关键词：

ANAPLASTIC THYROID-CANCER; ACQUIRED-RESISTANCE; BRAF INHIBITION; MEK INHIBITION; TUMOR-GROWTH; QUANTIFICATION; CARFILZOMIB; VEMURAFENIB; MECHANISMS; PATHWAYS;

D O I：

10.1158/1078-0432.CCR-19-1606

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2022 / 2036

页数：15

共 42 条

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