Abstract A231: Combination of MET and EGFR inhibitors in patient-derived tumor xenografts.

Abstract

Abstract The MET receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the development and progression of several human cancers and are suitable targets for cancer therapy. Similar to EGFR-targeted drugs, highly sensitive tumors are rare, and the reasons for response to MET-targeting agents are not yet clear. We studied patient-derived tumor xenografts and cell lines for their ex vivo and in vivo sensitivity against the small molecule MET inhibitors SGX-523, PF-04217903 and JNJ-38877605 tested in monotherapy, or in combination with the EGFR inhibitor erlotinib. Molecular characterization of the tumors was done to understand the basis of sensitivity or resistance. Ex vivo chemsosensitivity analysis was carried out in 68 tumors of 15 histotypes using a soft agar colony formation assay. The most sensitive patient-derived xenografts belonged to adeno lung cancer (LXFA 526, LXFA 623, LXFA 1647), liver cancer (LIXF 658), and renal cancer (RXF 616). The most sensitive cell line-derived xenografts belonged to Asian gastric cancer (MKN45, NUGC-4), Asian liver cancer (JHH-2, HLE), and prostate cancer (PC3M). IC50 values in the most sensitive models were in the nanomolar range for SGX-523 (32 − 406 nM), PF-04217903 (21 − 431 nM), and JNJ-38877605 (26 − 206 nM). Some sensitive tumors showed overexpression of the receptor MET on the RNA and protein level due to amplification of the gene; e.g. the NSCL adenocarcinoma LXFA 526 and LXFA 1647. The ligand HGF was highly expressed on the RNA and protein level, for example in the sensitive NSCL tumor LXFL 1121. Some MET positive tumors did not require MET activity for clonogenic growth, as despite a particularly high expression of MET, they were resistant to MET inhibitors (LXFL 1176, RXF 1220). LXFL 1176 carries an activating mutation of KRAS which could cause independence from MET signaling. Detailed ex vivo investigations on the effect of the combination of MET inhibitors SGX-523, PF-04217903 and JNJ-38877605 with erlotinib on tumor colony formation of 4 cell lines revealed synergistic effects on some (LXFA 526, LXFL 1121), but not other (MKN45, LXFA 1647) models, and the results were reproduced using cell suspensions of the respective tumor xenografts. Ten further tumor models, which were selected based on monotherapy results, were also treated with erlotinib, SGX-523 and the combination. In two additional models, the NSCL adenocarcinoma LXFA 623 and the pleuramesothelioma PXF 541, the combination of erlotinib and SGX-523 was beneficial. The benefit of combining SGX-523 and erlotinib in MET-expressing tumors as observed ex vivo could be confirmed in vivo, e.g. in the adeno lung cancer LXFA 526. Erlotinib as single agent marginally exerted antitumor efficacy (75 mg/kg, day 0–20 bid, T/C = 68%) whereas SGX-523 was active with T/C = 17% (60 mg/kg, day 0–20 bid) and, interestingly erlotinib at the same dosage increases the efficacy of SGX-523 significantly, causing tumor regression (T/C = 1%). In conclusion, the data support that selected NSCL, gastric, liver, and renal cancers are sensitive to MET inhibition due to defined genetic alterations. The combination of MET and EGFR inhibitors may have high clinical potential. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A231.