CRM1 and BRAF Inhibition Synergize and Induce Tumor Regression in BRAF-Mutant Melanoma

Abstract

Resistance to BRAF inhibitor therapy places priority on developing BRAF inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms of resistance. The CRM1 receptor mediates the nuclear export of critical proteins required for melanoma proliferation, survival, and drug resistance. We hypothesize that by inhibiting CRM1-mediated nuclear export, we will alter the function of these proteins resulting in decreased melanoma viability and enhanced BRAF inhibitor antitumoral effects. To test our hypothesis, selective inhibitors of nuclear export (SINE) analogs KPT-185, KPT-251, KPT-276, and KPT-330 were used to induce CRM1 inhibition. Analogs PLX-4720 and PLX-4032 were used as BRAF inhibitors. Compounds were tested in xenograft and in vitro melanoma models. In vitro, we found CRM1 inhibition decreases melanoma cell proliferation independent of BRAF mutation status and synergistically enhances the effects of BRAF inhibition on BRAF-mutant melanoma by promoting cell-cycle arrest and apoptosis. In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition. Mechanistic studies show that CRM1 inhibition was associated with p53 stabilization and retinoblastoma protein (pRb) and survivin modulation. Furthermore, we found that BRAF inhibition abrogates extracellular signalregulated kinase phosphorylation associated with CRM1 inhibition, which may contribute to the synergy of the combination. In conclusion, CRM1 inhibition impairs melanoma survival in both BRAF-mutant and wild-type melanoma. The combination of CRM1 and BRAF inhibition synergizes and induces melanoma regression in BRAF-mutant melanoma.

XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer

“…For that reason, our in vitro experiments using selinexor were generally performed after 24 hours of treatment. Marked synergy was observed when selinexor was used with a variety of chemotherapies and targeted therapies including platinum, B-Raf inhibitors, topoisomerase II inhibitors, proteasome inhibitors, etc (34,39,40). However, whether selinexor synergizes with radiation and its underlying mechanism has not been studied yet.…”

“…The selective inhibitor of nuclear export (SINE), selinexor (KPT-330), has demonstrated antitumoral activity with good tolerability in several preclinical cancer models (33)(34)(35)(36). Thus, selinexor is currently under investigation as a novel radiosensitizer for rectal cancer (ClinicalTrials.gov Identifier: NCT02137356) prompting the need to identify the radiosensitizer activity of selinexor in preclinical models of rectal cancer as well as its underlying mechanism.…”

First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

“…Preclinical evaluation of selinexor in combination therapies, with platins, taxanes, irinotecan, temozolomide, gemcitabine, vemurafenib, and ABT737, demonstrated enhanced efficacy in mouse xenograft models. [29][30][31][32][33][34] In addition, selinexor acted synergistically with radiation therapy in non-small-cell lung cancer to enhance cell death, at least in part through the inhibition of DNA damage repair enzymes. 35 Together, these data highlight the potential for selinexor in combination with commonly used therapeutic regimens and warrant further investigation of selinexor in clinical trials, some of which are currently ongoing.…”

Promising SINEs for Embargoing Nuclear–Cytoplasmic Export as an Anticancer Strategy

“…In addition, given the noted synergistic effects on cytotoxicity in neoplastic cells, the potential for combining XPO1 inhibition with conventional chemotherapy, such as topoisomerase inhibitors, is open for exploration in the future ( 21 , 73 , 86 ). Moreover, combination strategies with other targeted therapeutics may be another option for consideration, and recent preclinical data showing that combined XPO1 and BRAF inhibition leads to synergistic tumor regression in BRAF -mutant melanoma suggest that this may be a viable therapeutic approach as well ( 87 ).…”