KRAS mutation has been known as crucial marker for growth and maintenance of
pancreatic cancer (PC) and targeting the KRAS is inevitable component for realizing
precision medicine to PC. We established patient-derived
tumor cells (PDCs) from patient with KRAS G12R mutant PC. Through the PDC, we investigated the therapeutic impact of
sorafenib alone, LEE001 alone and the combination of
sorafenib and LEE001 in KRAS mutant PC. For the validation, we also tested a cell viability assay for
sorafenib, LEE001, and
sorafenib plus LEE001 in KRAS G12R transfected HEK293T cells. Based on MTT proliferation assays using PDCs, values of IC50 were 6.07 uM to
sorafenib and > 10.00 uM to LEE001, respectively. The value of IC50 of the combination (
sorafenib plus LEE001) was 3.19 uM. Cell proliferation of PDC was significantly inhibited by
sorafenib plus LEE001, as compared to
sorafenib monotherapy and LEE001 monotherapy. In the validation through KRAS G12R transfected HEK293T cells, consistent to findings in PDCs, combinations of
sorafenib plus LEE001 had most effective inhibitory effect in KRAS G12R transfected HEK293T cells. Furthermore, on analyzing the regulation of targeted downstream pathways upon exposure to
sorafenib, LEE001, and
sorafenib plus LEE001 by immunoblot assay using KRAS G12R transfected HEK293T cells, AKT phosphorylation was distinctively decreased in KRAS G12R transfected HEL293 cells after only
sorafenib plus LEE001. This study suggests that the combination of RAF and CDK4/6 inhibitors might be a novel treatment strategy for KRAS G12R mutant
pancreatic cancer. The antitumor effect of RAF plus CDK4/6 inhibitors also needs to be evaluated in other subtypes of KRAS mutation in
pancreatic cancer.