2025 Proffered Presentations
S083: IDENTIFICATION OF SIGNALING PATHWAYS ASSOCIATED WITH RESISTANCE TO INDUCTION CHEMOTHERAPY IN SINONASAL UNDIFFERENTIATED CARCINOMA
Yoko Takahashi, PhD1; Frederico O Gleber-Netto, MSc, DDS, PhD1; Diana Bell, MD2; Dianna Roberts, PhD1; Shirley Y Su, MD1; Ehab Y Hanna, MD1; 1The University of Texas MD Anderson Cancer Center; 2University of Pittsburgh
Background: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer that arises in the nasal cavity and paranasal sinuses. Despite aggressive multimodal therapy the prognosis remains poor. Because of its locally advanced nature, induction chemotherapy has been used in our institution to downstage loco-regionally advanced tumors before definitive surgery or radiation therapy. Unfortunately, nearly 30% of SNUC patients do not respond to induction chemotherapy, and this event is associate with poor survival rate. Therefore, developing strategies to overcome resistance to induction chemotherapy is crucial. In this study, we aimed to identify signaling pathways associated with resistance to induction chemotherapy in SNUC patients to develop strategies for overcoming this resistance.
Materials and Methods: Thirteen formalin-fixed, paraffin-embedded SNUC samples harvested after induction chemotherapy were used in this study. All the patients were treated at MD Anderson Cancer Center. Gene expression analysis was performed on an HTG EdgeSeq Oncology Biomarker Panel consisting of 2560 genes. Differentially expressed genes (DEGs) were identified by Wilcoxon Two-Sample Test using a 0.05 threshold, and pathway analyses were performed using Gene Set Enrichment Analysis (GSEA, version 4.3.3) and Qiagen Ingenuity Pathway Analysis (IPA).
Results: By comparing eight responders and five non-responders, we identified 126 DEGs. Hierarchical clustering analysis using these 126 genes demonstrated distinct gene expression profiles for the responders and non-responders. GSEA considering the molecular signatures in the Canonical Pathways gene set showed enrichment of pathways related to 1. Extracellular matrix organization, 2. Collagen synthesis, 3. Integrin beta1 pathway, and 4. MET pathway in non-responders. GSEA considering the Hallmark gene set demonstrated upregulation of 1. Epithelial-mesenchymal transition, 2. Angiogenesis, 3. Hypoxia, 4. Glycolysis, and 5. TGF Beta signaling. On the other hand, responders presented the upregulation of 1. the cytochrome P450 pathway and 2. the cytokine-cytokine receptor interaction pathway. IPA canonical pathways also showed upregulation of integrin cell surface interactions, extracellular matrix organization, MET signaling, and collagen biosynthesis. IPA upstream analysis indicated the activation of upstream regulators, including TGFB1 and HIF1A, in non-responders, supporting the results of GSEA analysis. Targeting some of these pathways might be a potential novel therapeutic strategy to overcome resistance to induction chemotherapy in SNUC patients.
Conclusion: We identified several signaling pathways associated with response to induction chemotherapy in SNUC patients. Since some of them are potentially targetable, this study may help us develop therapeutic strategies to improve the treatment outcomes of non-responders.