Synergistic Effect Between Erlotinib and MEK Inhibitors in KRAS Wild-type Human Pancreatic Cancer Cells

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2011 Mar 10

PMID 21385921

Citations 43

Authors

Caroline H Diep

Ruben M Munoz

Ashish Choudhary

Daniel D Von Hoff

Haiyong Han

Affiliations

Soon will be listed here.

Abstract

Purpose: The combination of erlotinib and gemcitabine has shown a small but statistically significant survival advantage when compared with gemcitabine alone in patients with advanced pancreatic cancer. However, the overall survival rate with the erlotinib and gemcitabine combination is still low. In this study, we sought to identify gene targets that, when inhibited, would enhance the activity of epidermal growth factor receptor (EGFR)-targeted therapies in pancreatic cancer cells.

Experimental Design: A high-throughput RNA interference (RNAi) screen was carried out to identify candidate genes. Selected gene hits were further confirmed and mechanisms of action were further investigated using various assays.

Results: Six gene hits from siRNA screening were confirmed to significantly sensitize BxPC-3 pancreatic cancer cells to erlotinib. One of the hits, mitogen-activated protein kinase (MAPK) 1, was selected for further mechanistic studies. Combination treatments of erlotinib and two MAP kinase kinase (MEK) inhibitors, RDEA119 and AZD6244, showed significant synergistic effect for both combinations (RDEA119-erlotinib and AZD6244-erlotinib) compared with the corresponding single drug treatments in pancreatic cancer cell lines with wild-type KRAS (BxPC-3 and Hs 700T) but not in cell lines with mutant KRAS (MIA PaCa-2 and PANC-1). The enhanced antitumor activity of the combination treatment was further verified in the BxPC-3 and MIA PaCa-2 mouse xenograft model. Examination of the MAPK signaling pathway by Western blotting indicated effective inhibition of the EGFR signaling by the drug combination in KRAS wild-type cells but not in KRAS mutant cells.

Conclusions: Overall, our results suggest that combination therapy of an EGFR and MEK inhibitors may have enhanced efficacy in patients with pancreatic cancer.

Citing Articles

Bufadienolides from Chansu Injection Synergistically Enhances the Antitumor Effect of Erlotinib by Inhibiting the KRAS Pathway in Pancreatic Cancer.

Guo Y, Jin Y, Gao J, Wang D, Wang Y, Shan L Pharmaceuticals (Basel). 2025; 17(12.

PMID: 39770538 PMC: 11677899. DOI: 10.3390/ph17121696.

G3BP2 promotes tumor progression and gemcitabine resistance in PDAC via regulating PDIA3-DKC1-hENT in a stress granules-dependent manner.

Xing F, Li B, Fang Y, Liang C, Liu J, Wang W Acta Pharmacol Sin. 2024; 46(2):474-488.

PMID: 39289547 PMC: 11746999. DOI: 10.1038/s41401-024-01387-5.

ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression.

Zhang H, Sun Y, Wang Z, Huang X, Tang L, Jiang K Nat Commun. 2024; 15(1):4642.

PMID: 38821916 PMC: 11143236. DOI: 10.1038/s41467-024-49105-3.

Genetic Signature of Human Pancreatic Cancer and Personalized Targeting.

Reshkin S, Cardone R, Koltai T Cells. 2024; 13(7.

PMID: 38607041 PMC: 11011857. DOI: 10.3390/cells13070602.

Radiation-Activated Cobalamin-Kinase Inhibitors for Treatment of Pancreatic Ductal Adenocarcinoma.

Gendron L, Sheveland C, Gunn J, Pogue B, Shell T, Shell J Mol Pharm. 2023; 21(1):137-142.

PMID: 37989273 PMC: 11228961. DOI: 10.1021/acs.molpharmaceut.3c00667.

References

Iynedjian P . Molecular physiology of mammalian glucokinase. Cell Mol Life Sci. 2008; 66(1):27-42. PMC: 2780631. DOI: 10.1007/s00018-008-8322-9. View

Petty W, Dragnev K, Memoli V, Ma Y, Desai N, Biddle A . Epidermal growth factor receptor tyrosine kinase inhibition represses cyclin D1 in aerodigestive tract cancers. Clin Cancer Res. 2004; 10(22):7547-54. DOI: 10.1158/1078-0432.CCR-04-1169. View

Rocha Lima C, Green M, Rotche R, Miller Jr W, Jeffrey G, Cisar L . Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol. 2004; 22(18):3776-83. DOI: 10.1200/JCO.2004.12.082. View

Massarelli E, Varella-Garcia M, Tang X, Xavier A, Ozburn N, Liu D . KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res. 2007; 13(10):2890-6. DOI: 10.1158/1078-0432.CCR-06-3043. View

Pratilas C, Hanrahan A, Halilovic E, Persaud Y, Soh J, Chitale D . Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res. 2008; 68(22):9375-83. PMC: 2649746. DOI: 10.1158/0008-5472.CAN-08-2223. View

Balko J, Jones B, Coakley V, Black E . MEK and EGFR inhibition demonstrate synergistic activity in EGFR-dependent NSCLC. Cancer Biol Ther. 2009; 8(6):522-30. DOI: 10.4161/cbt.8.6.7690. View

Laurent-Puig P, Lievre A, Blons H . Mutations and response to epidermal growth factor receptor inhibitors. Clin Cancer Res. 2009; 15(4):1133-9. DOI: 10.1158/1078-0432.CCR-08-0905. View

Yeh T, Marsh V, Bernat B, Ballard J, Colwell H, Evans R . Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007; 13(5):1576-83. DOI: 10.1158/1078-0432.CCR-06-1150. View

Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais M . Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007; 96(8):1166-9. PMC: 2360149. DOI: 10.1038/sj.bjc.6603685. View

10.

Buck E, Eyzaguirre A, Barr S, Thompson S, Sennello R, Young D . Loss of homotypic cell adhesion by epithelial-mesenchymal transition or mutation limits sensitivity to epidermal growth factor receptor inhibition. Mol Cancer Ther. 2007; 6(2):532-41. DOI: 10.1158/1535-7163.MCT-06-0462. View

11.

Chang Q, Chen E, Hedley D . Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models. Cancer Biol Ther. 2009; 8(20):1893-901. DOI: 10.4161/cbt.8.20.9430. View

12.

Iynedjian P . Mammalian glucokinase and its gene. Biochem J. 1993; 293 ( Pt 1):1-13. PMC: 1134312. DOI: 10.1042/bj2930001. View

13.

Scheithauer W, Schull B, Ulrich-Pur H, Schmid K, Raderer M, Haider K . Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol. 2002; 14(1):97-104. DOI: 10.1093/annonc/mdg029. View

14.

Baselga J, Arteaga C . Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005; 23(11):2445-59. DOI: 10.1200/JCO.2005.11.890. View

15.

Ley R, Balmanno K, Hadfield K, Weston C, Cook S . Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem. 2003; 278(21):18811-6. DOI: 10.1074/jbc.M301010200. View

16.

Moore M, Goldstein D, Hamm J, Figer A, Hecht J, Gallinger S . Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2007; 25(15):1960-6. DOI: 10.1200/JCO.2006.07.9525. View

17.

Jimeno A, Rubio-Viqueira B, Amador M, Grunwald V, Maitra A, Iacobuzio-Donahue C . Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer. Mol Cancer Ther. 2007; 6(3):1079-88. DOI: 10.1158/1535-7163.MCT-06-0448. View

18.

Adjei A, Cohen R, Franklin W, Morris C, Wilson D, Molina J . Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008; 26(13):2139-46. PMC: 2718422. DOI: 10.1200/JCO.2007.14.4956. View

19.

Buck E, Eyzaguirre A, Rosenfeld-Franklin M, Thomson S, Mulvihill M, Barr S . Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. Cancer Res. 2008; 68(20):8322-32. DOI: 10.1158/0008-5472.CAN-07-6720. View

20.

Deng J, Shimamura T, Perera S, Carlson N, Cai D, Shapiro G . Proapoptotic BH3-only BCL-2 family protein BIM connects death signaling from epidermal growth factor receptor inhibition to the mitochondrion. Cancer Res. 2007; 67(24):11867-75. DOI: 10.1158/0008-5472.CAN-07-1961. View