Abstract 2344: PDX from the naïve NSCLC patients containing activating EGFR mutations are resistant to erlotinib but sensitive to c-met inhibitor
Authors: Mengmeng Yang, Jiangyun Deng, Xiaoming Song, Jie Cai, Taiping Chen, Yiyou Chen, Henry Q.X. Li
Journal: Cancer Research (2012)

Abstract NSCLC is a common cancer with the highest mortality and few effective treatment options, except for the patients with EGFR (Erlotinib, Iressa) and ALK (Crizotinib) activating mutations. Recent studies indicated that some patients with the activating EGFR mutations but without pre-exposure to EGFR tyrosine kinase inhibitors (TKIs) are resistant to TKIs. The proposed mechanisms (1) include: T790M gatekeeper mutation preventing accessing the kinase activation site, Kras mutation, pTEN loss (2), or c-met amplification (3) that activates ERBB3 signaling (4). Patient Derived Xenograft (PDX) models have been suggested to more closely represent patient tumors (5, 6). We established several PDXs, including HuPrime® LU858, LU859, LU357, LU387, LU1901 and LU2503, using tumor tissues from individual NSCLC patients. LU858/859 contain the “classic” activating EGFR mutation, L858R; LU1868 contain L858R/T790M double mutations; LU357/LUF387 contain the common exon 20 insertion (2319-2320 AACCCCCAC); and LU1901/2503 have wild type EGFR. To our surprise, the two models with single L858R mutation, just like the model with double mutations, respond to the erlotinib poorly, as seen in some of clinic cases (1). Since they do not have T790M and Kras mutation, we examined them for c-met status, finding that their c-met gene are significantly amplified with also increased c-met/HGF expression as measured by at mRNA and protein levels (IHC), consistent with those seen in clinic (3). Furthermore, LU357 is sensitive to erlotinib while LU387 is not, corresponding to no c-met amplification in LU357 but significant amplification in LU387. All these suggest that the observed erlotinib resistance in these models could potentially be attributed to c-met signaling activation via c-met/HGF autocrine. To this end, we treated LU858, LU859 and LU2503 (also with c-met amplification) with c-met inhibitor, Crizotinib. Indeed, Crizotinib caused significant tumor response as expected in all these models. In particular, the combination treatment of LU858 and LU859 with erlotinib caused complete tumor regression by overcoming the resistance, suggesting a new potential effective treatment option. The results using PDX models can potentially help to design a prospective human study to demonstrate improved efficacy by the combination treatment via patient stratification to include the naïve NSCLC patient subjects with c-met amplification/EGFR mutation. 1. A. F. Gazdar, Oncogene 28 Suppl 1, S24, 2009 2. M. L. Sos et al., Cancer Res 69, 3256, 2009 3. T. Kubo et al., Int J Cancer 124, 1778, 2009 4. A. B. Turke et al., Cancer Cell 17, 77, 2010. 5. L. Ding et al., Nature 464, 999, 2010 6. E. Marangoni et al., Clin Cancer Res 13, 3989, 2007 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2344. doi:1538-7445.AM2012-2344