(P 185) CANCER TESTIS ANTIGENS AS TARGETS IN KIT11-MUTATED, IMATINIB-RESISTANT GIST

Objective: Treatment of gastrointestinal stromal tumors (GIST) involves tyrosine kinase inhibitors (TKIs) such as imatinib (IM) which are directed against KIT and PDGFRA. However, TKI-independent approaches are lacking. We sought to identify alternate therapeutic targets in IM-resistant (IM-res) tumors with KIT exon 11 mutations (KIT11-mut) using a bioinformatics approach.

Methods: As described by Vitiello et al (2019), samples from 75 patients with resected GIST underwent RNA sequencing. Counts were TPM-normalized, log-transformed, and correlated with clinicopathologic data. Differential gene expression (DGE) was performed using DESeq2. Genes of interest were defined as demonstrating log2 fold change (logFC) > 2, and adjusted p < 0.05. DGE analysis compared 1) KIT- vs. PDGFRA-mutated (mut) tumors, and 2) IM-untreated/sensitive (IM-u/s) vs. IM-res KIT11-mut tumors. Pathway analysis was performed using Cluster Profiler. R version 4.5.0 was used.

Results: A number of cancer testis antigens (CTAs) were among the most overexpressed genes in KIT-mut tumors (n=41) as compared with PDGFRA-mut tumors (n=24): MAGEA3 (logFC = 21), MAGEA6 (8.1), MAGEC2 (7.7), MAGEA1 (5.8), MAGEB17 (5.0), and MAGEC3 (2.6). PDGFRA-mut tumors were enriched in genes involved in regulation of membrane potential, chemotaxis, and ERK1/2 signaling. Subsequent DGE analysis revealed that among the most overexpressed genes in KIT11-mut IM-res (n=15) tumors, as compared with IM-u/s tumors (n=22), were MAGEA6 (logFC = 6.7), MAGEA3 (6.4), and MAGEA12 (4.8). 17/37 (45.9%) of KIT11-mut tumors expressed 1 or more MAGE gene. IM-res KIT11-mut tumors were enriched in genes involved in nuclear division, organelle fission, and cytoskeleton/intermediate filament organization.

Conclusion: CTAs are overexpressed in KIT-mut GIST as compared with PDGFRA-mut GIST, with nearly half expressing at least 1 MAGE gene and notable overexpression of MAGEA3. Both MAGEA3 and MAGEA6 were overexpressed in KIT11-mut IM-res tumors, which also demonstrated typical hallmarks of aggressiveness on pathway analysis. Given the recent success of T cell therapies directed against CTAs, and a lack of treatments for GIST beyond TKIs, further investigation is warranted to determine if CTA expression can be exploited in novel therapeutic approaches.