BioCentury
ARTICLE | Distillery Therapeutics

Cancer

November 6, 2017 7:51 PM UTC

Patient sample, cell culture and mouse studies suggest inhibiting PAK1 or PAK4 could help treat drug-resistant BRAF-mutant melanoma. In tumor samples from metastatic melanoma patients, high primary tumor levels of PAK1 were associated with acquired resistance to inhibitors of BRAF or BRAF plus MEK. In BRAF-mutant human melanoma cell lines resistant to BRAF inhibitors or combinations of BRAF and MEK inhibitors, siRNA targeting PAK1, shRNA targeting PAK4, a retroviral vector encoding an inactive PAK1 variant, or a pan-PAK inhibitor tool compound decreased viability compared with control siRNA/shRNA, empty vector or no treatment. In a patient-derived xenograft (PDX) mouse model of BRAF-mutant melanoma resistant to BRAF and MEK inhibitors, the pan-PAK inhibitor decreased tumor growth compared with vehicle. In the PDX model and a xenograft mouse model of BRAF-mutant melanoma resistant to BRAF and MEK inhibitors, the combination of the BRAF, MEK and pan-PAK inhibitors decreased tumor growth compared with the combination of BRAF and MEK inhibitors, and in the xenograft model, the three-inhibitor combination increased survival. In a xenograft mouse model of BRAF-mutant melanoma resistant to BRAF inhibitors, the combination of the BRAF and pan-PAK inhibitors decreased tumor growth and increased survival compared with the BRAF inhibitor alone. Next steps could include identifying and testing PAK1- and PAK4-specific inhibitors in the models...