at-13387 and Colorectal-Neoplasms

Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.. Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.. Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m. HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Melanoma; Mitogen-Activated Protein Kinase Kinases; Mutation; Oximes; Protein Kinase Inhibitors; Proteomics; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Cell division cycle 37 (Cdc37) is known to work as a kinase-specific cochaperone, which selectively regulates the maturation of kinases through protein-protein interaction (PPI) with Hsp90. Directly disrupting the Hsp90-Cdc37 PPI is emerging as an alternative strategy to develop anticancer agents through a specific inhibition manner of kinase clients of Hsp90. Based on a first specific small-molecule inhibitor targeting Hsp90-Cdc37 PPI (

Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Chaperonins; Colorectal Neoplasms; G1 Phase Cell Cycle Checkpoints; HSP90 Heat-Shock Proteins; Humans; Mice, Inbred BALB C; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Protein Binding; Structure-Activity Relationship; Sulfonamides