Mage-A Mediate Resistance To Chemotherapy In Multiple Myeloma Through Regulation Of Bcl-2 Proteins

Type I Melanoma Antigen Genes of the MAGE-A family are commonly expressed in multiple myeloma (MM). Their frequency of expression is higher in patients who have relapsed after chemotherapy compared to newly diagnosed patients, with a significant association with progression of disease. MAGE were also associated with high-risk disease in gene expression profiling studies. They belong to the Cancer-Testis group of oncofetal genes that are normally restricted to germ cells and trophoblastic tissue, and are aberrantly expressed in a broad range of human cancers. Type I MAGE proteins partner with the RING domain protein Kap1 to form ubiquitin ligase complexes, and in laboratory models of solid tumors they ubiquitinylate cancer-associated targets involved in metabolism, autophagy, and metastasis. We demonstrated that expression of MAGE-A genes, especially MAGE-A3, was correlated with progression of disease in MM and that MAGE-A inhibit p53-dependent and independent apoptosis in MM cells. These results lead us to investigate the hypothesis that MAGE-A promote resistance to chemotherapy-induced apoptosis in MM cells. We performed gene expression profiling by RNAseq of primary tumor specimens from an open label phase 2 clinical trial of panobinostat, a pan-HDAC inhibitor approved for treatment of relapsed MM, in combination with lenalidomide and dexamethasone (NCT01651039). These GEP data were analyzed for differential expression based on progression free survival (PFS) 90 days (long PFS). MAGE-A1 was the most overexpressed gene in the short PFS group compared to long ( p p 69/77 -Bim. These results demonstrate that MAGE-A/Kap1 is a key regulator of Bim that promotes survival of MM cells. Loss of MAGE-A also resulted in increased protein levels of Mcl-1 and decreased protein expression of Bcl-2. No significant changes in Bid or Bcl-xl proteins were observed and PUMA was not detected under these conditions. These results support a model in which MAGE-A mediates resistance to panobinostat and other chemotherapeutic agents through differential regulation of protein expression of Bim, Mcl-1, and Bcl-2. Therefore, MAGE-A is a promising novel therapeutic target, and inhibition of its anti-apoptotic activity may directly induce apoptosis or increase sensitivity to chemotherapy-induced apoptosis. Disclosures Cho: Ludwig Institute for Cancer Research: Membership on an entity9s Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Agenus, Inc.: Research Funding; Bristol-Myers Squibb: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech Roche: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Chari: Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding. Jagannath: Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Merck: Consultancy.