Abstract 816: Aurora kinase A inhibition overcomes tolerance to panHER inhibitors in HPV positive HNSCC

Abstract The incidence of HPV-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) has been increasing in recent decades. The EGFR inhibitor cetuximab (CTX) is less active in HPV+ than HPV- HNSCC. HPV oncoproteins E6 and E7 induce HER3 overexpression, and EGFR-HER3 heterodimer-driven survival signaling via PIK3, AKT and ERK1-2 contributes to resistance to cetuximab and the EGFR inhibitor erlotinib. We demonstrate that although panHER inhibitors afatinib and dacomitinib more effectively inhibit growth of HPV+ HNSCC cells than do erlotinib or cetuximab, adaptive signaling through the AURKA/PLK1 axis mediates resistance to panHER inhibitors. We hypothesized that combined panHER and AURKA inhibition would synergize to overcome persistence of HPV+ HNSCC. We find that HPV+ HSNCC cells UM-SCC47 and UPCI:SCC154 express both EGFR and HER3. Indeed, cell viability experiments and clonogenic survival assays demonstrate strong synergy between panHER and AURKA inhibitors, confirmed in xenografted tumor models treated with the second generation AURKA inhibitor VIC-1911 and dacomitinib. We then performed RNAseq and shotgun proteomics to understand the cellular mechanisms behind our combination. Dacomitinib had expected effects downregulating Hallmark G2M and EGFR phosphorylation targets, upregulating EMT markers and cell death markers. In contrast, addition of AURKA inhibition upregulated PLK1 and pPLK1 and cell death markers. These findings indicate that combination therapy with AURKA inhibition will mitigate the adaptability to EGFR and panHER inhibitors previously described for HPV+ HNSCC. Citation Format: Sebastian Cruz-Gomez,Jong Woo Lee,Julian Barrantes,Richard Ivey,Sara Savage,Pratima Chaurasia,Gunner Dickson,Dickson Adah,Bing Zhang,Amanda Paulovich,Barbara Burtness. Aurora kinase A inhibition overcomes tolerance to panHER inhibitors in HPV positive HNSCC [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 816.