Posted: Monday, May 8, 2023
Somponnat Sampattavanich, PhD, of Mahidol University, Bangkok, Thailand, and colleagues previously demonstrated the utility of comprehensive drug response and panomic profiling in identifying repurposable drug shortlists and developed the CCA45 gene-expression signature to predict prognosis in Asian patients with cholangiocarcinoma. A further analysis of therapeutic candidates and possible resistance mechanisms, which was presented during the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 6588/21), highlighted the potential of precision medicine in this clinical context.
The investigators established CCA1 cell lines resistant to either MEK or SRC inhibitors. Proteins associated with the cell cycle, apoptosis, MAPK, and mTOR were found to be upregulated in both MEK and SRC inhibitor–resistant cells. Src pathway activity seemed to be more significantly reduced in SRC inhibitor–resistant cells. Using systematic drug screening, the investigators identified CDK4/6 inhibitors as second-line therapeutic candidates for MEK inhibitor–resistant cells; SRC inhibitor–resistant cells exhibited cross-resistance to MEK inhibitors and sensitivity to a limited number of CDK4/6 inhibitors.
The investigators used a digital spatial profiling–based spatial transcriptomic platform panel, which can measure 17 of the 45 genes required by the CCA45 signature, to compare the tumor microenvironment in chemotherapy-sensitive versus chemotherapy-resistant disease; of these genes, ITGB4, FGFR3, VEGFC, NOTCH1, and RRAD exhibited significant changes in their expression levels with reductions in tumor percentage. The tumor microenvironment in gemcitabine/cisplatin responders displayed negative regulation of ERK1/2 and MAPK, high Wnt pathway activity, and high levels of tumor-infiltrating lymphocytes, whereas high neutrophil-related activity, high levels of nuclear factor–kappa B and regulatory T cells, and the exhausted immune phenotype were observed in nonresponders.
Disclosure: The study authors reported no conflicts of interest.