on-01910 and Melanoma

While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF. Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.. NCT01205815 (Sept 17, 2010).

Topics: Animals; Antineoplastic Agents; CD40 Antigens; Female; Glycine; Humans; Immune Checkpoint Inhibitors; Male; Melanoma; Mice; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; raf Kinases; ras Proteins; Signal Transduction; Sulfones; Xenograft Model Antitumor Assays

RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.

Topics: Animals; Apoptosis; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; F-Box-WD Repeat-Containing Protein 7; Gene Deletion; Glycine; HEK293 Cells; Humans; MAP Kinase Signaling System; Melanoma; Mice; Prognosis; Protein Stability; Proteolysis; Proto-Oncogene Proteins B-raf; Sulfones; Ubiquitin Thiolesterase; Vemurafenib