Bromodomain inhibition overcomes treatment resistance in distinct molecular subtypes of melanoma

• Published in: Proceedings of the National Academy of Sciences - PNAS 2022-08, Vol.119 (34), p.1-7
• Main Authors: Dar, Altaf A., Bezrookove, Vladimir, Nosrati, Mehdi, Ice, Ryan, Patino, John M., Vaquero, Edith M., Parrett, Brian, Leong, Stanley P., Kim, Kevin B., Debs, Robert J., Soroceanu, Liliana, Miller, James R., Desprez, Pierre-Yves, Cleaver, James E., Salomonis, Nathan, McAllister, Sean, Kashani-Sabet, Mohammed
• Format: Article
• Language: English
• Subjects: Anticancer properties; Apoptosis; Biological Sciences; Cell division; Cell Line, Tumor; Combinatorial analysis; DNA damage; Drug Resistance, Neoplasm - genetics; Gene regulation; Gene sequencing; Humans; Immunotherapy; Kinases; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Mitogen-Activated Protein Kinase Kinases; Mutants; Nuclear Proteins; Protein kinase; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - metabolism; Therapy; Transcription Factors; Tumors; Xenografts; Xenotransplantation
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2206824119

Therapy of BRAF-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF-mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS- and NF1-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.