Abstract 5630: Treatments of NSCLC-PDX with c-MET gene amplification by c-MET inhibitors lead to rapid development of drug resistance.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Drug resistance is one of important factors limiting effect of most cancer therapies. Understanding mechanisms causing resistance can facilitate overcoming resistance. c-MET gene activation, via either activating mutations or gene amplification, is an oncogenic driver for some non-small cell lung cancers (NSCLC) in patients as well as in patient derived xenograft (PDX) ([1][1]). c-MET gene activation is also one of the two most dominant TKI-resistance seen among the patients treated with EGFR-TKI (tyrosine kinase inhibitors) ([1][1], [2][2]). Therefore, c-MET inhibitor could become an important treatment option for NSCLC patients whose c-MET is either de nova activated or activated during TKI treatment ([1][1]). We recently demonstrated that Crizotinib (PF2341066), an approved drug against NSCLC with ALK-fusion and a known c-MET inhibitor, can effectively treat NSCLC with c-MET gene amplification, including those resistant to EGFR-TKIs ([1][1]), in PDXs. Specifically, we described two models LU1901 and LU2503 – both with amplified gene, accompanied with over-expression, of c-MET, and both sensitive to Crizotinib (complete regression in LU2503, while near-complete regression in LU1901) ([1][1]), confirming the c-MET activation as dominant oncogenic driver for these two tumors. In the present study, interestingly, the treated LU1901 tumors subsequently re-emerge and re-grow even in the presence of continuous treatment. In particular, the re-growed LU1901 become completely resistant to Crizotinib (we call LU1901R), even after it was re-engrafted. Pharmacodynamic analysis revealed that the LU1901R tumor has similar level of phosphorylation (or activation) of c-MET as the parental LU1901. Crizotinib treatment caused nearly-similar inhibition of c-MET in both LU1901 and LU1901R, as well as the downstream signaling, including pMEK and pAKT by Crizotinib in both LU1901 and LU1901R tumors along with c-MET inhibition. All these suggest that the threshold of c-MET activation for prompting tumor growth/survival is significantly lower in LU1901R than LU1901. We are currently characterizing the LU1901R in order to identify the mechanisms of resistance, and attempt to find approach to overcome them. In summary, we have successfully developed c-MET inhibitor resistant models that may reflect resistance emergence in the clinics. These models could be particularly useful in investigating clinical resistant mechanisms and evaluating new therapy that can overcome resistance. Citation Format: Mengmeng Yang, Xiaoming Song, JIe Cai, Youzhu Wang, Taiping Chen, Jean-Pierre Wery, Yiyou Chen, Henry Li. Treatments of NSCLC-PDX with c-MET gene amplification by c-MET inhibitors lead to rapid development of drug resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5630. doi:10.1158/1538-7445.AM2013-5630 [1]: #ref-1 [2]: #ref-2