ES 04.01 Novel Targetable Oncogenes in Lung Cancer

Abstract

Aberrations of oncogenes, such as EGFR mutation; and ALK and ROS1 fusions, function as a driver in the development of lung adenocarcinoma (LADC) and are established therapeutic targets. We previously identified RET fusion present in 1-2% of LADC (Kohno, Ichikawa, Nat Med, 2012). Its activity as an oncogenic driver in lung carcinogenesis was validated by a study of transgenic mice expressing KIF5B-RET cDNA in their lungs (Saito, Carcinogenesis, 2014). RET fusion is likely to be another target of therapy using tyrosine kinase inhibitors, as represented by a high response rate of RET-fusion positive LADC to vandetanib (LURET study, Yoh et al., Lancet Resp Med, 2016). Our genome-wide sequencing study revealed that ALK, RET and ROS1 oncogene fusion-positive LADCs carry less numbers of mutations in cancer-related genes than others (Saito, Cancer Res, 2015), indicating a small mutation burden in the development of the formers. On the other hand, >30% of LADC and most of other types of lung cancers are negative for the oncogene aberrations above, therefore, other therapeutic targets are needed for precision lung cancer medicine. We have revealed frequent inactivation of chromatin-regulating genes, such as SMARCA4/BRG1 and CREBBP, in lung cancers negative for oncogene aberrations (Ogiwara et al, Cancer Discovery, 2016). We propose a synthetic lethal therapeutic method for chromatin regulator-deficient lung cancers based on inhibition of paralog proteins. LADC driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). We recently revealed that variations in HLA-class II loci underlie the risk of the disease, by conducting a genome-wide association study of 3,173 EGFR-LADC patients and 15,158 controls (Shiraishi et al., Nature Comm, 2016). The result indicates that LADC develops in vivo through interaction between somatic oncogene mutations and germline variations that modulate immune reaction. We would like to discuss here precision lung cancer medicine based on information on cancer and the host genomes. RET fusion, synthetic lethal therapy, lung cancer risk