Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid tumors and one of the leading causes of cancer death world-wide. PDAC patients have the poorest prognosis with a median survival of less than 6 months and a 5-year survival rate of less than 5%. Despite detailed genetic mapping of PDAC, there are currently no effective targeted therapies for the disease. More than 95% of PDAC harbor an activating mutation in the KRAS gene. Several attempts on targeting each effector molecule in MEK- and PI3K- pathways, which are well-validated effector pathways in KRAS mutant cancer, have been made. However, none of the monotherapies have shown to be efficacious due to resistance and reprogramming. Hence, in this study we used a drug sensitivity based functional approach to identify combination strategies to render RAF/MEK/ERK- and PI3K/AKT/mTOR- targeted therapies efficacious against KRAS-driven PDAC. Thirty KRAS-mutant patient derived cell lines were screened against an in-house drug library of 525 clinically relevant small molecule anti-cancer agents in combination with RAF/MEK/ERK and PI3K/AKT/mTOR inhibitors, to identify synergistic/synthetic lethal partners to LY3009120 (RAF inhibitor), trametinib (MEK inhibitor), SCH772984 (ERK inhibitor), alpelisib (PI3K inhibitor), ipatasertib (AKT inhibitor), everolimus (mTOR inhibitor). Promising drug combinations from the initial screen were re-evaluated in 8X8 dose response matrices. In parallel, RNA sequencing was carried out on the cell lines to stratify the combination treatment strategies against PDAC. One of the most striking synergies seen was between the RAF/MEK/ERK inhibitors and mitosis/ microtubule-targeting agent vincristine. The combination of a MEK inhibitor trametinib and vincristine selectively induced cell death in a subset of the PDAC cell lines (25%). A correlation was observed between a selective effect of the combination and high expression levels of INKA1, a tumor suppressor and endogenous inhibitor of PAK4. The result therefore suggests that PAK4 activity is an important negative regulator of cell death triggered by the trametinib-vincristine combination. In summary, we identified trametinib + vincristine as a selective drug combination for a subset of KRAS-mutant PDAC with a putative predictive biomarker (INKA1 expression), which holds a potential for clinical translation, hence requires further exploration.
Citation Format: Prson Gautam, Markus Vähä-Koskela, Max Tomlinson, Adrienne D. Cox, Channing J. Der, Tero Aittokallio, Krister Wennerberg. Drug screening and molecular profiling identifies INKA1 as a predictive biomarker for sensitivity to MAPK inhibition-antimitotic combination treatment in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A137. doi:10.1158/1535-7163.TARG-19-A137