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Recent advances in molecular biology have led to the identification of new molecular targets, such as EGFR mutations and EML4-ALK fusion gene, in lung cancer. Dramatic response has been achieved with EGFR-TKI (gefitinib and erlotinib) and an ALK-TKI (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major clinically relevant mechanisms of acquired resistance to EGFR-TKI are gatekeeper mutation, Met amplification, and increased expression of HGF. Additionally, we reported that EGF receptor ligands activate EGFR as a bypass signal and induce crizotinib resistance in EML4-ALK lung cancer cells. Hsp90 is a molecular chaperone that plays a central role in regulating the correct folding, stability of client proteins, including mutant EGFR, EML4-ALK, and also Met, wild-type EGFR which cause ligand triggered resistance to TKIs. Hsp90 inhibition is therefore thought to be a promising strategy for overcoming resistance of EGFR-TKI and ALK-TKI. Moreover, a BIM deletion polymorphism was reported to be a novel mechanism of resistance to EGFR-TKI. BIM is a BH3-only proapoptotic protein, and its upregulation is required for apoptosis induction by EGFR-TKI. Notably, a BIM deletion polymorphism occurs naturally in 12.9% of East Asian individuals, impairing the generation of the proapoptotic isoform required for the EGFR-TKI therefore conferring an inherent drug-resistant phenotype. We reported HDAC inhibitor vorinostat could increase expression of the proapoptotic BH3 domain-containing isoform of BIM, which was sufficient to restore gefitinib death sensitivity in the EGFR mutant, EGFR-TKI resistant cells. Our results show that HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in cases of EGFR mutant lung cancer where resistance to EGFR-TKI is associated with a common BIM polymorphism.

Lung cancer with epidermal growth factor receptor (EGFR) activating mutations, such as exon 19 deletion and exon 21 L858R point mutation, responds to the EGFR-tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib. Recent clinical trials demonstrated much longer progression-free survival for EGFR mutant lung cancer patients when treated with gefitinib and erlotinib compared with conventional chemotherapy. Therefore, EGFR-TKIs are recommended as first-line therapy for EGFR mutant lung cancer patients by lung cancer practice guideline in the Japan Lung Cancer Society and in National Comprehensive Cancer Network. However, almost without exception, the responders relapse after various times due to acquiring resistance to EGFR-TKIs. Recently, several mechanisms were reported to induce acquired resistance to reversible EGFR-TKIs for lung cancer with EGFR-activating mutations. Of these, the secondary T790M mutation in EGFR is the most investigated cause of acquired resistance to the reversible EGFR-TKIs. Irreversible EGFR-TKIs were expected to overcome the reversible EGFR-TKI resistance of lung cancer caused by T790M mutation in EGFR. On the other hands, the novel resistant mechanisms, such as MET amplification and HGF overexpression, are also found. We have shown that the combined therapy of MET inhibitor and EGFR-TKI overcome caused by these mechanisms. More recently, mutant EGFR selective EGFR-TKIs, which are active to mutant EGFR with exon 19 deletion, L858R, and T790M but not wild-type EGFR, have been developed. In this symposium, we will overview the molecular mechanisms of EGFR-TKI resistance and discuss novel therapeutic strategies that are under development for overcoming the resistance in lung cancer.

Recent advances in molecular biology have led to the identification of new molecular targets for solid tumors, which were considered refractory to conventional cancer therapy, and efficacious molecular targeted drugs are being developed. For example, oncogenic drivers such as EGFR mutations, ALK rearrangement, ROS1 rearrangement, and RET rearrangement have been found in lung cancer, and dramatic therapeutic effects have been achieved with corresponding drugs in lung cancer expressing these driver oncogenes. On the other hand, patients who have responded to those inhibitors will acquire resistance within a few years and experience the recurrence of cancer, and several molecular targets for overcoming the resistance have also been identified. Using lung cancer as an example, new molecular targets will be introduced in this session.

Dramatic response has been achieved with EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib), in EGFR mutant lung cancer. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to EGFR-TKIs include gatekeeper mutations in EGFR and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand-triggered receptor activation as well. For example, hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells. These observations indicate that signals from oncogenic drivers (EGFR signaling) and ligand-triggered bypass signals (HGF-Met) must be simultaneously blocked to avoid the resistance. This talk will focus specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies using HGF-Met inhibitors that are under development for overcoming resistance to EGFR-TKIs in lung cancer.

Japan Clinical Oncology Group (JCOG) is the largest cooperative group in Japan. The yearly accrual of 2011 was 2744 in total. Currently, there are 30 trials on accrual and 20 trials on follow-up. Those trials are supported by about 40 staffs including 5 physicians in JCOG DC/OPS. JCOG has now 15 study groups and has an established peer-review system for protocol and adverse events. There are 180 participating institutions and all roster information is managed in JCOG DC/OPS. JCOG DC/OPS issues monitoring reports for all studies twice a year. Until now, 25 JCOG studies were adopted as a reference of various cancer treatment guidelines.Current challenges in JCOG DC/OPS are as follow: (i) streamlining study process. The project for protocol development acceleration has been activated since 2009. The speed has been improved afterward and the shortest duration from concept approval to protocol approval is 173 days. Acceleration of manuscript writing is also underway. (ii) Correlative studies and biospecimen repository. Recently the demand for correlative studies is growing. We have implemented several correlative studies along with regular JCOG studies and accumulated the know-how in such type of studies. In addition, JCOG biospecimen repository has been established and specimens are to be collected under the common procedure before long. (iii) Promotion of ‘Kodo-iryo’ trials. JCOG is now planning two ‘Kodo-iryo’ trials (clinical trials using the evaluation system of investigational medical care). We are now developing a standardized procedure for conducting future ‘Kodo-iryo’ trials more smoothly. (iv) International collaborative trials. JCOG is now conducting two international collaborative studies. The harmonization of database definitions is sometimes hard and the number of staffs is not enough to handle many international trials. (v) Introduction of remote data entry system. In JCOG, all forms are still paper-based. It is mainly due to few supports by clinical research coordinator in the participating institutions. On the other hand, the yearly accrual becomes more and now we are considering introducing remote data entry system. Through all of those challenges, we aim to conduct well-designed, high-quality clinical trials rapidly and establish a large number of new standard treatments for cancer patients.

Purpose Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR mutant lung cancer cells by activating Met and the downstream PI3K/Akt pathway. Moreover, continuous exposure of HGF accelerates emergence of EGFR-TKI-resistant clones. The present study was carried out to determine whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. Experimental design The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992) and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR-mutant human lung cancer cell lines PC-9 and HCC827 with exon 19 deletion, and H1975 with T790M secondary mutation. As an in vivo model, PC-9 cells mixed with HGF-producing fibroblasts, MRC-5, were subcutaneously inoculated into SCID mice and the therapeutic effects of E7050 combined with gefitinib were examined. Results Our results indicated that E7050 circumvented resistance to all of the reversible, irreversible and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 combined with gefitinib-induced marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. Conclusions A new Met kinase inhibitor, E7050, reverses three different mechanisms of gefitinib resistance induced by HGF, suggesting the usefulness of E7050 for overcoming HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.