Hiroyuki Mano

After graduation from The University of Tokyo Medical School at 1984, I became a physician for clinical hematology, and also started my career as a researcher to study how genetic abnormalities contribute to human carcinogenesis. My research group discovered NRAS mutations among myelodysplastic syndrome (Nature 327:430, 1987), and I discovered a novel, non-receptor type protein-tyrosine kinase TEC (Oncogene 5:1781, 1990). I then revealed that TEC kinase is involved in the intracellular signaling for B-cell receptor (PNAS 96:11976, 1999), and that TEC together with BTK (another member of the TEC family kinases) are essential for the normal B-lymphocyte development (J Exp Med 192:1611, 2000). Having such series of research activities, when I became an independent researcher at Jichi Medical University, I started a novel project to identify essential growth drivers in human cancer. For this aim, we developed a highly sensitive retroviral cDNA expression library, and, by using this functional screening system, tried to isolate transforming genes directly from human cancer specimens. Such approach led us to discover EML4-ALK fusion-type oncogene in lung cancer (Nature 448:561, 2007), and the target validity of EML4-ALK was further confirmed in our transgenic mice treated with an ALK inhibitor (PNAS 105:19893, 2008). Our series of translational research instantly triggered the development of ALK-specific inhibitors among pharmaceutical companies. We further developed companion diagnostics for EML4-ALK–positive tumors, a sensitive immunohistochemical assay (Clin Cancer Res 15:3143, 2009) and multiplex RT-PCR (Clin Cancer Res 14:6618, 2008), both are used in current clinical setting. The first inhibitor that underwent clinical trials was crizotinib that gave the response rate of ~60% in the phase I/II trials. US FDA approved this drug at 2011, only 4 years after our discovery of EML4-ALK, and this was the record-breaking speed in the history for any anticancer drugs. We were the first to reveal a crizotinib–resistant mechanism of cancer. Deep sequencing of the specimens before and after the relapse during the treatment with crizotinib revealed two amino acid substitutions within the kinase domain of EML4-ALK only in the relapsed phase. Both of the mutations turned out to confer resistance against crizotinib (NEJM 363:1734, 2010), and, interestingly, one of the mutation sites was at the identical position (the “gatekeeper” position) to Thr-790 in EGFR that is the most frequent mutation site for the acquired resistance against gefitinib. Many 2nd generation ALK inhibitors have been developed to conquer the gatekeeper mutation, and some of them, ceritinib and alectinib, already approved in US and Japan, respectively. Notably, alectinib gave a magical 94% response rate in phase I/II trials. So our work has led to the realization of the most effective drug against human epithelial malignancies. Importantly, EML4-ALK was the first fusion-type tyrosine kinases in major epithelial tumors that provoked two research fields; (1) discovery of other fusion kinases in epithelial tumors, including our own isolation of RET fusions and ROS1 fusions (Nat Med 18:378, 2012), and (2) analyses of ALK on other epithelial tumors, including our own discovery of activating point mutations of ALK in neuroblastoma (Nature 455:971, 2008). These analyses further raised a new concept of cancer classification scheme, beyond-organ and gene-based “ALKoma” (Cancer Discov 2:495, 2012). This is one of beginning of cancer genomic medicine. Also, it is our delight that our research has directly saved the life of thousands of lung cancer patients already, and will do so for hundreds of thousands of individuals in the coming decade. Our research activities have expanded to examine other cancers, and did identify oncogenic RAC1 mutations (PNAS 110:3029, 2013) and DUX4-IGH fusion oncogene in acute lymphoblastic leukemia in adolescents and young adults (Nat Genet 48:569, 2016). For the era of cancer genomic medicine, we have just published an article to introduce the MANO method that enables a high-throughput functional annotation for hundreds of “variants of unknown significance” in the cancer genome (Sci Transl Med 9:eaan6556, 2017). Further, marked amplification of RAS-MAPK pathway genes were recently identified in linitis plastics-type gastric cancer (Nature Cancer 2:962, 2021).