Evanny Marinovic

Low‐grade serous ovarian carcinoma (LGSOC) is a rare, indolent ovarian cancer subtype with limited effective therapies. Approximately 40% of cases lack canonical MAPK/ERK or PI3K/AKT/mTOR pathway alterations and are classified as having no specific molecular profile (NSMP). These patients have poor responses to chemotherapy, MEK inhibitors, and hormonal therapies, highlighting the need for alternative strategies. This study aimed to identify novel therapeutic targets in NSMP LGSOC. A high‐throughput drug screen of 3,436 compounds (including FDA‐approved, clinically tested, and investigational agents) was conducted across 12 LGSOC and one control ovarian epithelial cell line. EGFR inhibitors emerged as selective hits in NSMP cell lines and were further tested in two NSMP and two MAPK‐mutant lines in combination with standard‐of‐care chemotherapy agents, carboplatin and paclitaxel. EGFR expression was assessed using RNA sequencing, DNA methylation profiling, and immunohistochemistry in primary tumors, followed by survival analysis based on expression levels. Unsupervised clustering of drug response data revealed subtype‐specific vulnerabilities, with EGFR inhibitors showing marked cytotoxicity in all five NSMP lines (robust Z ‐score ≤ −2), and minimal activity in MAPK‐ and USP9X ‐mutant lines. EGFR inhibitors (avitinib, AV‐412) showed selective, low‐dose synergy with standard‐of‐care chemotherapy in NSMP models, with minimal and inconsistent effects in MAPK‐mutant lines. NSMP tumors showed elevated EGFR mRNA and EGFR protein expression, associated with poor survival, advanced disease stage, and peritoneal involvement, and inversely correlated with MAPK mutations. These findings position EGFR overexpression as a defining and targetable feature of NSMP LGSOC and support further preclinical validation of EGFR inhibitors as a treatment strategy for this understudied cancer subtype. © 2026 The Pathological Society of Great Britain and Ireland.