Abstract 5636: SKY-1214, a small molecule splicing modulator of members of the Fanconi anemia pathway, exerts anti-cancer activity both as single agent and in combination in multiple myeloma and non-Hodgkin's lymphoma
Authors: Simone Rauch, Stefan Reber, Montserrat Perez-Salvia, Marco Pregnolato, Botao Liu, Loren Berry, Olesia Buiakova, Hasane Ratni, Brian Gudenas, Carlo Cusulin, Lauren Shanahan, Davide Isaia, Corinna Spohr, Anna Groener, Joseph Duffy, Steven Taylor, Veronica Costa, Sergey Paushkin
Journal: Cancer Research (2025)

Abstract The growing multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL) patient population which becomes refractory to available treatments requires new, effective and convenient therapies with novel mechanisms of action. SKY-1214 is a small molecule that modulates splicing of FANCL and FANCI pre-mRNA, causing exon skipping and introduction of premature termination codons leading to the downregulation of FANCL and FANCI mRNAs and proteins. FANCL and FANCI are critical components of the Fanconi anemia DNA damage repair pathway, which contributes to maintenance of genomic integrity. SKY-1214 shows anti-cancer activity as single agent in multiple MM and NHL cell lines, including models of high-risk MM and NHL. In vivo, SKY-1214 treatment results in tumor growth inhibition and regression in MM and NHL cell line-derived xenograft (CDX) models. The combination of SKY-1214 with small molecule agents used for the treatment of MM and NHL, including vincristine, dexamethasone and selinexor, results in improved inhibition of cell growth and viability in multiple cell lines. In vivo, the combinations result in improved tumor growth inhibition and regression and increased durability of effect upon treatment cessation in CDX models. Here, we describe the results of in vitro combination studies of SKY-1214 with antibody-drug conjugates (ADC) and monoclonal antibodies. Cell growth and viability were assessed using cell viability assays (CellTiter-Glo2.0 or FACS-based assays) in tumor cells monoculture or in co-culture with T cells or NK cells to evaluate the combination with monoclonal antibodies. Combination of SKY-1214 with the BCMA-targeting ADC belantamab mafodotin shows additive and synergistic effect in specific concentration ranges resulting in enhanced cell killing in a panel of MM cell lines. Combination of SKY-1214 with bispecific antibodies, including αCD3-αBCMA, in co-culture with T cells shows additive effect. Additive effect is observed also for the combination of SKY-1214 with monoclonal antibodies in co-culture with NK cells. SKY-1214 treatment shows single agent anti-cancer activity in vitro and in vivo in MM and NHL models and combines well with small molecule agents, ADCs and monoclonal antibodies used for the treatment of these disorders. These data, together with the favorable oral bioavailability and pharmacologic characteristics of SKY-1214 with a distinctive mechanism of action, warrants future development in the clinic. Citation Format: Simone Rauch, Stefan Reber, Montserrat Perez-Salvia, Marco Pregnolato, Botao Liu, Loren Berry, Olesia Buiakova, Hasane Ratni, Brian Gudenas, Carlo Cusulin, Lauren Shanahan, Davide Isaia, Corinna Spohr, Anna Groener, Joseph Duffy, Steven Taylor, Veronica Costa, Sergey Paushkin. SKY-1214, a small molecule splicing modulator of members of the Fanconi anemia pathway, exerts anti-cancer activity both as single agent and in combination in multiple myeloma and non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5636.