Abstract 1700: Valproic acid potentiates the efficacy of anti-EGFR monoclonal antibodies in sensitive and resistant RAS/BRAF wild type colorectal cancer models

Abstract Background. Colorectal cancer (CRC) is a major global health issue, with fewer than 20% of metastatic CRC (mCRC) patients surviving beyond 5 years. Although, monoclonal antibodies (MoAbs) targeting EGFR, such as cetuximab or panitumumab (PAN), combined with chemotherapy, are standard treatments in RAS/BRAF wild type (wt) mCRC patients, their efficacy is limited by intrinsic and acquired resistance mechanisms. Here, we evaluated a novel therapeutic strategy, based on the repurposing of valproic acid (VPA), an anticonvulsant drug with histone deacetylase inhibitor and anticancer properties, in combination with anti-EGFR MoAbs, with or without irinotecan (IRI)-based chemotherapy, in CRC models. Methods. The antitumor effect was assessed in a panel of RAS/BRAF wt CRC cell lines, sensitive, intrinsically or acquired resistant to anti-EGFR MoAbs, by evaluating clonogenic growth, apoptosis and tumor spheroids formation. Acquired resistant models were characterized using biological assays and multi-omics approaches (proteomics, phosphoproteomics and metabolomics). Results. PAN-resistant models exhibited significantly higher proliferation rates in both 2D and 3D cultures, as well as increased migration compared to parental cells. An integrated multi-omics analysis revealed that secondary resistance to PAN was associated with metabolic alterations, extracellular matrix remodeling, impaired DNA damage repair pathways and alterations of growth factor receptors signaling. Interestingly, the combination of VPA and PAN with or without IRI-based chemotherapy induced synergistic antiproliferative and pro-apoptotic effects across all tested cell lines, including PAN-acquired resistant models. Mechanistically, VPA/PAN treatment led to a significant downregulation of pEGFR (Tyr1068) and its downstream signaling molecules, including pMAPK and pAKT, key drivers of anti-EGFR resistance, confirming multiomic data. In vitro and in vivo experiments are underway to confirm the ability of VPA to enhance anti-EGFR efficacy, overcome, delay or prevent resistance and provide further insights into the underlying molecular mechanisms. Based on these evidences, we launched the randomized phase 2 trial in mCRC patients in a third-line rechallenge setting (VICTORIA trial). In details, RAS/BRAF ctDNA wt patients are randomized to receive either standard rechallenge with IRI and PAN alone (ARM A) or in combination with VPA (ARM B). In patients in ARM A, at time of disease progression, a second study will explore if the addition of VPA to IRI and PAN might revert the resistance occurrence. Conclusions. Overall, our findings propose a novel therapeutic strategy for the management of mCRC patients that could optimize the treatment of RAS/BRAF wt mCRC patients and expand the continuum of care in later treatments lines. Citation Format: Roberta Affatato, Elena Di Gennaro, Alessandra Leone, Biagio Pucci, Susan Costantini, Rita Lombardi, Eleonora Perfetto, Maria Serena Roca, Francesca Bruzzese, Francesca Collina, Claudia Cardone, Tania Moccia, Elena Sinopoli, Antonio Avallone, Alfredo Budillon. Valproic acid potentiates the efficacy of anti-EGFR monoclonal antibodies in sensitive and resistant RAS/BRAF wild type colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1700.