Abstract LB-245: The EGRF receptor inhibitor Erlotinib, alone or in combination with the rexinoid LG100268, is effective for prevention in mouse models of lung and pancreatic cancer with Kras mutations
Authors: Liby Karen T. , Williams Charlotte R. , Risingsong Renee , Sporn Michael B. , Collins Ryan M. , Royce Darlene B. 
Published: May 2015

Abstract
Lung cancer and pancreatic cancer are leading causes of cancer deaths, with extremely poor 5 year survival rates for both types of cancer. The epidermal growth factor receptor (EGFR) and its ligands regulate cell growth, and EGFR expression is frequently elevated in lung and pancreatic cancer. Tumors with activating mutations in EGFR are treated clinically with drugs such as erlotinib, a tyrosine kinase EGFR inhibitor. Up to 90% of pancreatic cancers and 35% of lung cancers contain activating mutations in Kras, but tumors with Kras mutations are usually resistant to EGRF inhibitors. Erlotinib is an approved drug for treating pancreatic cancer, but it only extends survival by a few weeks. We have previously shown that the rexinoid LG100268 (268) is effective for prevention of experimental lung and pancreatic cancers with Kras mutations, and a recent clinical trial suggests that the combination of a rexinoid and erlotinib might be useful for treating lung cancer, even in tumors with Kras mutations. In order to test whether this combination of drugs might be useful for prevention of lung cancer, female A/J mice were injected i.p. with vinyl carbamate (16 mg/kg) once a week for two weeks. The carcinogen induces Kras mutations and microscopic adenocarcinomas in the lungs within 4-6 weeks. Starting one week after the last injection of carcinogen, the mice were fed the rexinoid 268 (40 mg/kg diet), erlotinib (150 mg/kg diet) or the combination for 16 weeks. All 3 groups significantly (P &lt; 0.05 for each group vs. control and the combination vs. the individual drugs) reduced the average size of lung tumors by 45-80%, from an average of 3.2 ± 0.6 mm3 in the control group (n = 28) to 1.8 ± 0.4 with erlotinib, 1.1 ± 0.3 with 268 and 0.7 ±0.08 mm3 with the combination (n = 12 per group). The average tumor burden was also significantly reduced 43% by erlotinib, 77% by 268 and 85% by the combination. The total tumor burden per slide was 10.5 ± 1.5 mm3 in the control group but only 2.5 ± 0.5 mm3 in mice fed 268, 6.0 ±1.0 in mice fed erlotinib, and 1.6 ± 0.3 mm3 in mice fed the combination (P &lt; 0.05). The percentage of high grade invasive tumors was also significantly (P &lt; 0.05) reduced from 51% in the control group to 22-34% in mice on a chemopreventive diet. In the LSL-KrasG12D/+;LSL-Trp53R127H/+;Pdx-1-Cre (KPC) mouse model of pancreatic cancer, Kras mutations drive carcinogenesis, and the clinical symptoms and histopathology found in this model replicate the human disease. To test the effectiveness of an EGFR inhibitor in the KPC model, mice were fed erlotinib (150 mg/kg diet), beginning at 4 weeks of age until the mice displayed overt symptoms (cachexia, abdmoninal distension) of pancreatic cancer. Erlotinib significantly (P &lt; 0.05) increased survival compared to the control group (n = 26-27 per group). Average lifespan was extended from an average of 24.7 ± 2.4 weeks in the control group vs. 29.3 ± 2.8 weeks in mice on erlotinib diet, an increase of 4.5 weeks. Ongoing experiments are testing the efficacy of the combination of erlotinib and 268 in the KPC model and studying the mechanism of action of these drugs in Kras-driven models.
Citation Format: Karen T. Liby, Charlotte R. Williams, Renee Risingsong, Michael B. Sporn, Ryan M. Collins, Darlene B. Royce. The EGRF receptor inhibitor Erlotinib, alone or in combination with the rexinoid LG100268, is effective for prevention in mouse models of lung and pancreatic cancer with Kras mutations. [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-245. doi:10.1158/1538-7445.AM2014-LB-245