Annual Report 2021

Division of Translational Genomics (Kashiwa Campus)

Susumu S. Kobayashi, Akihiro Ohashi, Kosuke Tanaka, Tomoko Yamamori, Ryo Kamata, Jie Liu, Miho Ishizaka, Chiaki Mashima, Miyuki Yoshiya, Yuta Sakae, Kei Oguchi, Takuma Hayashida, Toyohiro Yamauchi, Gaku Yamamoto, Hiroko Nagayama

Introduction

 The Division of Translational Genomics was restructured and started when Susumu Kobayashi was recruited to the NCC in April 2018. We closely collaborate with intramural and extramural clinicians and researchers to develop genome biomarker diagnostics, explore rational molecular targets for anti-cancer therapies, and elucidate molecular mechanisms of tumorigenesis, progression, and therapeutic responses.

The Team and What We Do

 Our dream is to conquer cancers, and we work hard to achieve it. In addition to our weekly laboratory meetings, we have combined weekly meetings with the Division of Translational Informatics. We also participate in the center-wide research meetings and invite outside speakers to present the most up-to-date science.

Research activities

 For the past decade, molecular-target drugs have been game-changers for cancer therapeutic strategies. In most cases, however, these therapies fail due to intrinsic and acquired drug resistance. We are interested in studying mechanisms of action and resistance mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer using multi-omics analyses, single cell analyses, and mathematical modeling. In collaboration with pharmaceutical companies, we evaluated several novel EGFR TKIs in lung cancer patients with EGFR exon 20 mutations. In addition, we study genomic instability, one of the cancer hallmarks. We are interested in the mechanisms by which aberrant DNA replication and repair play crucial roles in tumorigenesis. Deeply understanding “Cancer Hallmarks and Vulnerability” is important to discover the target molecules for novel drug development.

Clinical trials

 We have participated in several clinical trials to support translational aspects of studies.

Education

 We have accepted and trained the following trainees: Graduate students from the University of Tokyo and staff physicians and residents of the National Cancer Center Hospital East. We gave a few educational seminar presentations at the University of Tokyo.

Future Prospects

 In collaboration with other divisions in the NCC, other institutions, and pharmacological companies, we will investigate mechanisms of action and resistance to targeted therapies including immune-checkpoint inhibitors. We will also continue to investigate genomic instability in cancers and identify molecules that determine vulnerability. Our major goal is to identify and develop novel therapeutics to treat cancers through our research activities.

List of papers published in 2021

Journal

1. Du J, Kageyama SI, Yamashita R, Hirata H, Hakozaki Y, Okumura M, Motegi A, Hojo H, Nakamura M, Hirano Y, Sunakawa H, Minamide T, Kotani D, Tanaka K, Yano T, Kojima T, Ohashi A, Tsuchihara K, Akimoto T. Impacts of the STING-IFNAR1-STAT1-IRF1 pathway on the cellular immune reaction induced by fractionated irradiation. Cancer science, 113:1352-1361, 2022

2. Takei H, Coelho-Silva JL, Tavares Leal C, Queiroz Arantes Rocha A, Mantello Bianco T, Welner RS, Mishima Y, Kobayashi IS, Mullally A, Lima K, Machado-Neto JA, Kobayashi SS, Lobo de Figueiredo-Pontes L . Suppression of multiple anti-apoptotic BCL2 family proteins recapitulates the effects of JAK2 inhibitors in JAK2V617F driven myeloproliferative neoplasms. Cancer science, 113:597-608, 2022

3. Izumi H, Matsumoto S, Liu J, Tanaka K, Mori S, Hayashi K, Kumagai S, Shibata Y, Hayashida T, Watanabe K, Fukuhara T, Ikeda T, Yoh K, Kato T, Nishino K, Nakamura A, Nakachi I, Kuyama S, Furuya N, Sakakibara-Konishi J, Okamoto I, Taima K, Ebi N, Daga H, Yamasaki A, Kodani M, Udagawa H, Kirita K, Zenke Y, Nosaki K, Sugiyama E, Sakai T, Nakai T, Ishii G, Niho S, Ohtsu A, Kobayashi SS, Goto K. The CLIP1-LTK fusion is an oncogenic driver in non-small-cell lung cancer. Nature, 600:319-323, 2021

4. Kashima Y, Shibahara D, Suzuki A, Muto K, Kobayashi IS, Plotnick D, Udagawa H, Izumi H, Shibata Y, Tanaka K, Fujii M, Ohashi A, Seki M, Goto K, Tsuchihara K, Suzuki Y, Kobayashi SS. Single-Cell Analyses Reveal Diverse Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer. Cancer research, 81:4835-4848, 2021

5. Iwai K, Nambu T, Kashima Y, Yu J, Eng K, Miyamoto K, Kakoi K, Gotou M, Takeuchi T, Kogame A, Sappal J, Murai S, Haeno H, Kageyama SI, Kurasawa O, Niu H, Kannan K, Ohashi A. A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery. Science advances, 7:2021

6. Ishioka K, Yasuda H, Hamamoto J, Terai H, Emoto K, Kim TJ, Hirose S, Kamatani T, Mimaki S, Arai D, Ohgino K, Tani T, Masuzawa K, Manabe T, Shinozaki T, Mitsuishi A, Ebisudani T, Fukushima T, Ozaki M, Ikemura S, Kawada I, Naoki K, Nakamura M, Ohtsuka T, Asamura H, Tsuchihara K, Hayashi Y, Hegab AE, Kobayashi SS, Kohno T, Watanabe H, Ornitz DM, Betsuyaku T, Soejima K, Fukunaga K. Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer. Cancer research, 81:3916-3929, 2021

7. Tanaka K, Yu HA, Yang S, Han S, Selcuklu SD, Kim K, Ramani S, Ganesan YT, Moyer A, Sinha S, Xie Y, Ishizawa K, Osmanbeyoglu HU, Lyu Y, Roper N, Guha U, Rudin CM, Kris MG, Hsieh JJ, Cheng EH. Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis. Cancer cell, 39:1245-1261.e6, 2021

8. Sehgal K, Rangachari D, VanderLaan PA, Kobayashi SS, Costa DB. Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations. The oncologist, 26:281-287, 2021

9. Trinh BQ, Ummarino S, Zhang Y, Ebralidze AK, Bassal MA, Nguyen TM, Heller G, Coffey R, Tenen DE, van der Kouwe E, Fabiani E, Gurnari C, Wu CS, Angarica VE, Yang H, Chen S, Zhang H, Thurm AR, Marchi F, Levantini E, Staber PB, Zhang P, Voso MT, Pandolfi PP, Kobayashi SS, Chai L, Di Ruscio A, Tenen DG. Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML. Blood, 138:1331-1344, 2021

10. Ummarino S, Hausman C, Gaggi G, Rinaldi L, Bassal MA, Zhang Y, Seelam AJ, Kobayashi IS, Borchiellini M, Ebralidze AK, Ghinassi B, Trinh BQ, Kobayashi SS, Di Ruscio A. NAD Modulates DNA Methylation and Cell Differentiation. Cells, 10:2021

11. Kobayashi IS, Viray H, Rangachari D, Kobayashi SS, Costa DB. EGFR-D770>GY and Other Rare EGFR Exon 20 Insertion Mutations with a G770 Equivalence Are Sensitive to Dacomitinib or Afatinib and Responsive to EGFR Exon 20 Insertion Mutant-Active Inhibitors in Preclinical Models and Clinical Scenarios. Cells, 10:2021