LCL-161

Myelofibrosis (MF) is characterized by anemia, constitutional symptoms, hepatosplenomegaly and bone marrow fibrosis, and is associated with poor survival. The janus kinase inhibitor (JAKi) ruxolitinib has been the mainstay of treatment for over a decade. Despite demonstrated symptomatic and quality of life improvement, unmet clinical needs persist. A literature review identified promising novel targeted treatment options in MF using pre‐set selection criteria (available Phase 2 or 3 data, minimum enrollment of 50 patients, trial end date within the last 5 years). Available data for novel and approved therapies were extracted, tabulated, and analyzed for clinical relevancy. From an initial shortlist of 48, 16 retained molecules were selected for inclusion. Other JAKi (pacritinib, momelotinib, jaktinib) address treatment‐related cytopenia, expanding the therapeutic utility of this class of agents to patients with baseline anemia or thrombocytopenia. Novel candidates exploit multiple molecular pathways, and offer the potential to improve the management of MF‐associated cytopenia (imetelstat, pelabresib, navitoclax, selinexor, luspatercept, sotatercept, elritercept, LCL161, bomedemstat) and recover bone marrow fibrosis (imetelstat, pelabresib, navitoclax and bomedemstat). It remains to be seen if these newer agents can induce any remission in MF and enable patients to come off therapy, but the future is beginning to look much brighter.

Fragile X Mental Retardation Protein 1 (FMR1) is a translational repressor crucial for regulating genes in the central nervous system. While a lack of FMR1 expression causes Fragile X Syndrome (FXS), its overexpression is implicated in various cancers, necessitating tight regulation of FMR1 protein levels for normal cell physiology. In this study, we report that FMR1 is upregulated in gastric cancer patients. Reducing FMR1 expression decreased cell growth in gastric cancer cell lines. The Smac Mimetic LCL161 reduced both FMR1 and cellular inhibitor of apoptosis protein 2 (cIAP2) levels. Suppressing cIAP2, but not cIAP1, led to decreased FMR1, while cIAP2 overexpression increased FMR1 in gastric cancer cells. We observed that cIAP2 is also upregulated in gastric cancer patients, with FMR1 and cIAP2 levels positively correlated in both gastric and colorectal cancers. Notably, cIAP2 binds FMR1 via its CARD domain, unlike most cIAP2 targets that bind the BIR domain. Furthermore, cIAP2 ubiquitinates FMR1 through its CARD-RING domains, stabilizing the protein without proteasomal degradation. FMR1, modulated by cIAP2, promotes gastric cancer cell growth. Collectively, our findings highlight FMR1's growth-promoting role in gastric cancer and reveal a novel function of cIAP2 in stabilizing FMR1 as an E3 ligase. These results suggest targeting cIAP2 could be an effective strategy for treating gastric cancer by downregulating both cIAP2 and FMR1.