Assessment of EGFR-dependent signaling pathway targeting in EGFR-mutated and wild type non-small cell lung cancer patient-derived xenografts

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S130-S130
• Main Authors: De Plater, L, Deas, O, Guibaudet, C, Nicolas, A, Couturier, J, Zemoura, L, Bièche, I, Ouafi, L, Chapelier, A, Livartowski, A, De Cremoux, P, Daniel, C, Roman-Roman, S, Judde, J.G, Decaudin, D
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Cancer; Cancer therapies; Drug resistance; Effectiveness; Epidermal growth factor receptors; Hematology, Oncology and Palliative Medicine; Inhibition; Lung cancer; Monoclonal antibodies; Mutation; Non-small cell lung carcinoma; Patients; Pharmacology; Signal transduction; Signaling; Targeted cancer therapy; TOR protein; Translocation; Tumorigenesis; Tumors; Xenografts; Xenotransplantation
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32986-0

Background: EGFR mutations are found in 10% ol Caucasian and 30% of Asian non-small cell lung cancer (NSCLC) patients. Hence, EGFR-targeted therapies have been developed for EGFR inhibition with significant initial responses. However, acquisition of drug resistance is common when using an EGFR mono-targeting strategy, with half of the patients developing resistance within 12 months after starting treatment. While various mechanisms of acquired resistance have been identified, the best strategy against these resistances is not well defined. The aim of this study was to evaluate targeting of both Pi3K/mTOR and EGFR signaling pathways in a panel of NSCLC Patient-Derived Xenografts {PDXs) bearing various mutations. Material and Methods: Four well characterized PDXs obtained from NSCLC patient's were treated with the EGFR (HER1) TKI erlotinib (30 mg/kg/day, 5 days/week), the HER1/2/4 TKI afatinib (20 mg/kg/day. 5 days/week), the anti-EGFR monoclonal antibody cetuximab, (25mg/kg. twice a week), the MEK1/2 inhibitor selumetinib (25 mg/kg twice a day. 5 days/week), and/or the Pi3K p110α/β/δ/γinhibitor BKM120 (20 mg/kg/day. 5 days/week). All PDXs were adenocarcinomas. One model had an EGFR mutation exon 18 G719A (LCF29), one other had both EGFR mutation exon 21 L858R (LCF12) and PIK3CA mutation (exon 9 E545K), and the two last models were EGFR/PIK3CA wild-type tumors (LCF4 and LCF9). No EGFR nor ALK translocation, were found in these models. Results: The two EGFR-TKI erlotinib and afatinib induced significant Tumor Growth Inhibition (TGI) in both EGFR-mutated PDXs LCF29 and LCF12, with a higher efficacy of afatinib (91 % and 71 %) than of erlotinib (62% and 53%). In contrast, cetuximab had a slightly better efficacy in EGFR-mutated than in EGFR-wild type PDXs (LCF29: 24%, LCF12: 26%. LCF4" 6%, and LCF9: 11%). Cetuximab did not improve the efficacy of both erlotinib and afatinib. BKM120 induced contrasted TGI of 35% and 70% in the two EGFR-mutated PDXs, and significant TGI of 59% and 65% in the two Pi3K and EGFR wild-type tumors. In the EGFR- and PIK3CA-mutated LCF12 PDX, BKM120 was combined with the three EGFR-targeted treatments, showing a significantly increased TGI with eriotinib and afatinib (TGI of 88% and 92%, respectively), but not cetuximab. Finally, in these four models, selumetinib induced no significant TGI (0% to 40%). Conclusions: As observed in NSCLC patients, afatinib was superior to erlotinib which was superior to cetuximab. Moreover, while PIK3CA m