Consistent areas within the same tumor nodule are shown. crizotinib is usually superior to standard chemotherapy TDZD-8 in ALK inhibitor-nave disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance. == Introduction == EML4-ALKfusion accounts for approximately 4% of non-small cell lung cancer (NSCLC) (1,2). Crizotnib (3,4), an FDA-approved inhibitor of anaplastic lymphoma kinase (ALK), demonstrated efficacy in a phase II clinical trial in lung cancer patients with tumors harboringEML4-ALKrearrangements (5). Despite striking activity in early studies, TDZD-8 some reports have also noted impressive activity with chemotherapy in ALK-positive cancers (6,7). Indeed, retrospective analyses have suggested that time to progression on crizotinib is usually statistically similar to that achieved by first-line platinum-based chemotherapy (2,8,9). Thus, it was unclear if crizotinib Rabbit Polyclonal to AKR1A1 is usually superior to either first or second line chemotherapy in this subset of patients. These uncertainties were recently addressed by a phase III trial comparing crizotinib to chemotherapies in the second-line setting that definitively exhibited the superiority of crizotinib (10). Nonetheless, both primary and acquired resistance have been observed in patients treated with crizotinib (1114). Up to 30% ALK-positive patients do not respond to crizotinib treatment, while those who respond initially will eventually develop acquired resistance after prolonged treatment. Secondary mutations in the ALK kinase domain name have been identified in a subset of patients who become insensitive to crizotinib. Co-clinical trials, in which highly faithful genetically designed murine cancer models (GEMMs) are carefully randomized and used to mimic human clinical trials, have the TDZD-8 potential to provide mechanistic insights that impact the analysis of the concurrent human study (1520). In recent years, we as well as others have performed numerous treatment studies in GEMMs leading to identification of clinically relevant biomarkers and novel treatment methods, as well as successful prediction of clinical outcomes (2126). In particular, we have previously described a co-clinical trial using a murine model recapitulating human NSCLC driven by an activatingKrasmutation (21). The murine trial predicted the clinical superiority of combined selumetinib and docetaxel compared to docetaxel alone(27). Importantly, patient stratification and biomarker strategies identified from the murine trial have provided valuable insight for the design of subsequent clinical studies. In the present analysis, we have performed a murine co-clinical study mimicking the phase III clinical trial in ALK-positive patients with advanced disease who had received prior platinum-doublet-based first-line treatment. In this study, patients were TDZD-8 randomized to receive crizotinib or standard second-line therapy, including docetaxel or pemetrexed. Using novel murine models ofEML4-ALKNSCLC, we decided the short- and long-term efficacy of crizotinib treatment compared to docetaxel or pemetrexed. The results demonstrate the predictive power of EML4-ALK-driven murine lung adenocarcinoma models and validate their use for studying additional treatments for the ALK populace. Toward this end, we explored treatment with an HSP90 inhibitor and a second-generation ALK inhibitor to overcome either primary or acquired crizotinib resistance in order to anticipate their functions in the growing ALK armamentarium. == Materials and Methods == == Mice and treatment == Generation of bi-transgenic mice with lung-specific doxycycline-inducibleEML4-ALKexpression was described previously(28). Mice were subjected to magnetic resonance imaging (MRI) 46 weeks after initiation of a doxycycline-containing diet to determine baseline tumor volume. Mice with appropriate tumor burden were randomized to three groups and treated with crizotinib, pemetrexed or docetaxel. Crizotinib was delivered via daily oral feeding at 100 mg/kg in water..