Molecular alterations identified in a phase 1 study of fostamatinib plus paclitaxel in platinum-resistant ovarian cancer.

Abstract

e17609 Background: Resistance to chemotherapy remains a challenge in recurrent platinum-resistant ovarian cancer (PROC). While the spleen tyrosine kinase (SYK) inhibitor fostamatinib (Fos) combined with paclitaxel (wPac) has shown promising efficacy, the molecular mechanisms underlying resistance remain unclear. This study aimed to generate hypotheses regarding molecular alterations associated with resistance by analyzing pre- and post-treatment tumor samples from patients with partial response (PR) and progressive disease (PD). Methods: Tumor samples from 6 patients enrolled in a phase 1 study of Fos combined with wPac (3 PR and 3 PD) were analyzed with GeoMx Digital Spatial Profiling. Gene expression data were normalized using the upper quartile (Q3) method to account for technical bias. Differential gene expression and pathway enrichment analyses identified potential resistance mechanisms. Genes and pathways were prioritized based on statistical significance (adjusted p-values) and biological relevance. SYK, the primary target of fostamatinib, was manually reintegrated into the analysis after initial quality control filtering due to its therapeutic importance. Results: Molecular profiling revealed significant differential expression of genes in patients with PD compared to PR, including PTP4A1 (p=0.00205), CCNI (p=0.00205), RPL18A (p=0.00205), FURIN (p=0.00343), and ALDOA (p=0.00343). These genes are involved in processes such as cell proliferation, energy metabolism, and protein maturation, which may contribute to resistance. PTP4A1, a phosphatase that regulates cellular signaling pathways, could influence resistance by interacting with SYK and other proliferative signals. Pathway enrichment analysis using the Hallmark Gene Set Collection (MSigDB) identified suppression of MYC targets v1 (p=1.05e-33; NES=3.37), oxidative phosphorylation (p=4.14e-18; NES=2.90), mTORC1 signaling (p=6.59e-14; NES=2.68), and unfolded protein response (p=9.07e-9; NES=2.51) in patients with PD. These findings suggest altered energy metabolism and ribosomal dysfunction as potential contributors to resistance. Dysregulation of PTP4A1 and other genes involved in growth and metabolism may support resistance development. Conclusions: The molecular differences between patients with PR and PD to the Fos-wPac combination highlight potential resistance mechanisms, including alterations in energy metabolism, ribosomal dysfunction, and cellular proliferation. These findings provide groundwork for future validation studies to assess these pathways and genes as therapeutic targets in PROC. Clinical trial information: NCT03246074 .