Abstract 6588: Systems biology-based drug repositioning and biomarker discovery for Thai liver fluke-associated cholangiocarcinoma

Abstract

Our group has recently reported the successful use of comprehensive drug response and pan-omic profiling for identifying repurposable drug shortlists in Asian cholangiocarcinoma. We also developed the CCA45 gene-expression signature that could accurately predict the prognosis of CCA patients, especially those with Asian ethnic backgrounds. To further explore therapeutic candidates and potential resistance mechanisms, we have established CCA1 cell lines resistant to their subgroup-specific drug candidates: MEK and SRC inhibitors. Reverse-phase protein arrays (RPPA)-based proteomic profiling revealed upregulation of cell cycle, apoptosis, MAPK, and mTOR-related proteins in both MEKi- and SRCi-resistant cells. Src pathway activity was found to be more significantly reduced in SRCi-resistant cells. We identified CDK4/6 inhibitors as the second-line therapeutic candidates for MEK inhibitor-resistant cells by systematic drug screening. SRCi-resistant cells unexpectedly developed cross-resistance to MEK inhibitors and showed sensitivity to only a few CDK4/6 inhibitors. These data are beneficial for the clinical translation of our proposed drug candidates for Asian CCA, preparing the alternate regimens after drug resistance. We also adopted the DSP-based spatial transcriptomic platform to compare the tumor microenvironment between chemotherapy-sensitive and chemotherapy-resistant CCA patients. While the CTA panel showed consistent patterns of normalized gene expression to those of the WTA panel, the CTA panel can only measure 17 of the 45 genes required for our CCA45 signature. Out of these 17 genes, ITGB4, FGFR3, VEGFC, NOTCH1, and RRAD showed significant gene expression changes with reducing tumor percentage. The microenvironment of gemcitabine/cisplatin responder (R) non-responder (NR) exhibited negative regulation of ERK1/2 and MAPK, high WNT pathway activity, and high tumor-infiltrating lymphocyte (TIL). In contrast, the microenvironment of the non-responder (NR) subgroup showed high neutrophil-related activity, high NFκB, high Treg, and the exhausted immune phenotype. Overall, our study contributes toward realizing the precision medicine concept for CCA patients. Citation Format: Supawan Jamnongsong, Patipark Kueanjinda, Piyathida Tawornparcha, Kulthida Vaeteewoottacharn, Seiji Okada, Siwanon Jirawatnotai, Ananya Pongpaibul, Krittiya Korphaisarn, Somponnat Sampattavanich. Systems biology-based drug repositioning and biomarker discovery for Thai liver fluke-associated cholangiocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6588.