Antitumor activity of sorafenib plus CDK4/6 inhibitor in pancreatic patient derived cell with KRAS mutation

Lee, Taehyang; Kim, Kyung; Lee, Jeeyun; Park, Se Hoon; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Park, Joon Oh; Kim, Seung Tae

doi:10.7150/jca.26068

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J Cancer 2018; 9(18):3394-3399. doi:10.7150/jca.26068 This issue Cite

Research Paper

Antitumor activity of sorafenib plus CDK4/6 inhibitor in pancreatic patient derived cell with KRAS mutation

Taehyang Lee, Kyung Kim, Jeeyun Lee, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Joon Oh Park^✉, Seung Tae Kim^✉

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

✉ Corresponding authors: Seung Tae Kim, M.D., Ph.D., Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Tel.: +82-2-3410-1779; Fax: More

Citation:

Lee T, Kim K, Lee J, Park SH, Park YS, Lim HY, Kang WK, Park JO, Kim ST. Antitumor activity of sorafenib plus CDK4/6 inhibitor in pancreatic patient derived cell with KRAS mutation. J Cancer 2018; 9(18):3394-3399. doi:10.7150/jca.26068. https://www.jcancer.org/v09p3394.htm

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Abstract

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.

Keywords: KRAS mutation, CDK4/6 inhibitor, sorafenib, pancreatic cancer

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APA

Lee, T., Kim, K., Lee, J., Park, S.H., Park, Y.S., Lim, H.Y., Kang, W.K., Park, J.O., Kim, S.T. (2018). Antitumor activity of sorafenib plus CDK4/6 inhibitor in pancreatic patient derived cell with KRAS mutation. Journal of Cancer, 9(18), 3394-3399. https://doi.org/10.7150/jca.26068.

ACS

Lee, T.; Kim, K.; Lee, J.; Park, S.H.; Park, Y.S.; Lim, H.Y.; Kang, W.K.; Park, J.O.; Kim, S.T. Antitumor activity of sorafenib plus CDK4/6 inhibitor in pancreatic patient derived cell with KRAS mutation. J. Cancer 2018, 9 (18), 3394-3399. DOI: 10.7150/jca.26068.

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CSE

Lee T, Kim K, Lee J, Park SH, Park YS, Lim HY, Kang WK, Park JO, Kim ST. 2018. Antitumor activity of sorafenib plus CDK4/6 inhibitor in pancreatic patient derived cell with KRAS mutation. J Cancer. 9(18):3394-3399.

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