title: 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 signal-regulated 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.
authors.affiliation: Harvard Medical School, Boston, MA, USA.
authors.forename: Roberto A
authors.initials: RA
authors.lastname: Salas Fragomeni
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Chung
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.forename: William
authors.initials: W
authors.lastname: Senapedis
authors.forename: Jean-Richard
authors.initials: JR
authors.lastname: Saint-Martin
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.forename: James C
authors.initials: JC
authors.lastname: Cusack
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D048493:Proto-Oncogene Proteins B-raf; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D000097606:Exportin 1 Protein