Background: The diversity of cancer genome significantly influences drug response and impairs the discovery of biomarker for patient stratification. As important preclinical models, patient derived cell lines are widely used in drug discovery and biomarker screening, yet complicated by intratumoral heterogeneity.
Methods: We created a One Patient Panel (OPP), that is, a set of cell lines (26 lines in this case) derived from tumor tissue from one hepatocellular carcinoma (HCC) patient, and systematically integrated the OPP by transcriptional profiling, chromosomal copy number variations (CNVs) and whole-exome sequencing. The pharmacological profiles of more than 70 targeted therapeutic agents were also examined in OPP.
Results: CNVs data showed that 10 chromosomes contained no significant qualitative differences, while 13 chromosomes had obvious cytogenetical and cell-line specific alterations, among the 26 cell lines. Likewise, transcriptional profiling and drug response analysis indicated the presence of clinically relevant intratumoral heterogeneity in OPP. For examples, MEK pathway was highly active in 6 (23.1%) lines and completely inactive in 3 (11.5%) lines, mTOR pathway was active in about 50% of lines, and Sonic Hedgehog pathway was active in above 30% of lines. Yet, based on the drug screening data, 80% of drugs had similar response patterns among those lines in OPP, suggesting a close genetic background among them. Interestingly, FGFR and MEK inhibitors have dramatically distinct drug response patterns among those cell lines. In response to FGFR inhibitors, there were four sensitive lines with the IC50 lower than 250 nM and five resistant lines with IC50 higher than 5 μM. For MEK inhibitors, the IC50s of three sensitive lines were lower than 50 nM, while the resistant IC50s were higher than 1 μM. Thus, a maximum of 30-folds difference in sensitivity to targeted agents was observed among cell lines in OPP. Moreover, there were no overlaps between the two groups of sensitive lines to FGFR or MEK inhibitors. Despite response variations, different inhibitors against the same molecular target, such as BGJ398 (Novartis) and AZD4547 (Astrazeneca), both against FGFR, showed comparable sensitivity in the same cell lines, indicating those inhibitors might have same biomarker(s).
Conclusions: Taken together, the OPP recapitulates the intratumoral genetic, molecular and pharmacological heterogeneity in HCC. Importantly ,the OPP provides a powerful platform for optimizing drug selection and biomarker discovery, which may speed up the emergence of precision therapeutic regimens.
Citation Format: Qiang Gao, William Niu, Andrew Tse, Jeffrey Lin, Jian Zhou, Simon Shung, Jia Fan. Intratumoral heterogeneity and precise personalized therapy revealed by one patient panel in hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-223. doi:10.1158/1538-7445.AM2014-LB-223
