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Annual Report 2024

Division of Cellular Signaling

Shinji Kohsaka, Toshihide Ueno, Masachika Ikegami, Yosuke Tanaka, Yoshiyuki Suehara, Shuichi Watanabe, Hiroyuki Mano, Reina Takeyama, Saori Sugaya, Satoko Kaneko, Hiromi Takawashi

Introduction

 Through an approach combining high-sensitivity functional screening with next-generation sequencing analysis, we aimed at elucidating mechanisms of human tumorigenesis and developing novel molecularly targeted therapies.

The Team and What We Do

  • Identification of tumorigenesis and development of new drugs through comprehensive genome analysis.
  • Establishment of functional assay to evaluate gene alterations.
  • Development of new computational pipelines for cancer research.

    • Research Activities

     In collaboration with clinical research, we performed comprehensive analyses of malignant tumor specimens using next‑generation sequencing, and conducted studies of tumor characteristics along with cellular experiments. As a result, several findings were suggested to have potential clinical applicability. The main outcomes are described below.

    1) Confirmation of tumor-shrinking effect of the targeted protein degrader E7820 in J‑PDX (Japanese patient‑derived xenograft) models and initiation of an investigator‑initiated clinical trial

     E7820 and indisulam are sulfonamide molecular glue compounds that form a complex with DCAF15 to induce RBM39 degradation and thereby modulate RNA splicing. To evaluate the antitumor efficacy of E7820, we tested it in patient‑derived xenograft models and observed an objective response rate of 38.1%. Genomic analysis revealed that tumors harboring loss‑of‑function alterations in homologous recombination repair (HRR) genes were particularly sensitive to E7820. Transcriptome analysis showed that drug treatment led to downregulation of HRR‑related gene transcription and increased intron retention, accompanied by elevated DNA double‑strand breaks, suggesting that HRR deficiency results in synthetic lethality with E7820. These findings indicate that homologous recombination deficiency (HRD) may serve as a predictive biomarker for E7820 efficacy; the results were published (Kohsaka S. et al. 8, 1, 117, npj Precis Oncol. 2024).

    2) Genomic analysis of normal breast tissue from individuals at increased breast cancer risk

     Germline pathogenic variants in BRCA1/2 confer increased breast cancer risk, but there has been no clinical test to precisely quantify that risk. We hypothesized that clonal expansion may already begin in histologically normal breast tissue, so we collected normal tissue from breast cancer patients and BRCA mutation carriers for analysis. Genome sequencing and targeted panel analyses identified clones harboring recurrent oncogenic driver mutations, indicating the presence and expansion of clones even in normal breast tissue. We developed a "clonality score" to assess the prevalence and distribution of clonal expansions and found higher scores in individuals with a prior history of stage II or higher breast cancer. Large clones carried multiple mutations, and mutation count correlated with clone size. These results suggest that clonal changes can occur in normal breast tissue before tumors are detectable by pathology or imaging, and that the clonality score may be a useful metric for risk assessment and selection of preventive strategies (Hirose T, et al. 10, 1, 87, npj Breast Cancer. 2024).

    3) Preclinical efficacy evaluation of the irreversible HER2 TKI zongertinib

     ERBB2 (HER2) mutations occur in about 2–4% of non‑small cell lung cancers (NSCLC) and are associated with poor prognosis. Currently available HER2‑targeted tyrosine kinase inhibitors have limited efficacy or tolerability for HER2‑mutant NSCLC. In this work we discovered zongertinib, a covalent HER2 inhibitor. Zongertinib potently and selectively inhibits HER2 while sparing EGFR, suppressing growth of HER2‑dependent tumor cells. It showed antitumor activity in HER2‑ dependent NSCLC xenograft models and other HER2‑dependent cancers (e.g., cholangiocarcinoma and breast cancer), and enhanced efficacy when combined with antibody–drug conjugates or KRAS G12C inhibitors. These preclinical results support potential clinical efficacy in patients with HER2‑dependent tumors and have advanced the compound toward clinical development (Wilding B, et al. 15, 1, 119–138. Cancer Discov. 2024).

    4) Elucidation of resistance mechanisms to PARP inhibitors

     We built a screening platform covering 243 gene perturbations across 68 cancer‑related genes to dissect anticancer drug mechanisms and validated it using drugs targeting EGFR, BRAF, and MAP2K1. In BRCA2‑deficient cell lines we discovered that increased expression of SMO and GLI1 contributes to olaparib resistance. GLI1 overexpression upregulated DNA repair genes and was associated with PARP inhibitor resistance. GLI1 inhibitors were effective in these cells, and combination therapies showed synergistic effects. This platform can thus aid discovery of new therapeutic strategies and predictive markers for cancers with DNA repair defects (Ikeuchi H. et al. 43, 41, 3037-3048, Oncogene. 2024).

    5) Development of genomic data analysis platforms

     We released FELIS, an analysis platform for the C‑CAT clinical genomics database (felis‑portal.com). We also published HueTracer, software for inferring cell–cell interactions from spatial transcriptomics (github.com/MANO‑B/HueTracer), and released U3‑Nomogram, an algorithm to distinguish somatic from germline variants (github.com/MANO‑B/U3‑Nomogram).

    Education

     Two trainees from The University of Tokyo, two from Juntendo University, one from Yokohama City University, one from Hokkaido University, one from Kyushu University, and one from The Jikei University.

    Future Prospects

     Genomic medicine is now being implemented broadly in clinical practice, yet analytic technologies such as whole‑genome sequencing, long‑read sequencing, and single‑cell analysis continue to advance daily. Going forward, we aim to contribute to the further development of genomic medicine by advancing sequencing and screening technologies, developing algorithms for ultra‑low‑frequency variant detection, and identifying clinically useful biomarkers.

    List of papers published in 2024

    Journal

    1. Wilding B, Woelflingseder L, Baum A, Chylinski K, Vainorius G, Gibson N, Waizenegger IC, Gerlach D, Augsten M, Spreitzer F, Shirai Y, Ikegami M, Tilandyová S, Scharn D, Pearson MA, Popow J, Obenauf AC, Yamamoto N, Kondo S, Opdam FL, Bruining A, Kohsaka S, Kraut N, Heymach JV, Solca F, Neumüller RA. Zongertinib (BI 1810631), an Irreversible HER2 TKI, Spares EGFR Signaling and Improves Therapeutic Response in Preclinical Models and Patients with HER2-Driven Cancers. Cancer discovery, 15:119-138, 2025

    2. Outani H, Ikegami M, Imura Y, Nakai S, Takami H, Kotani Y, Inoue A, Okada S. Age-related genomic alterations and chemotherapy sensitivity in osteosarcoma: insights from cancer genome profiling analyses. International journal of clinical oncology, 30:397-406, 2025

    3. Ikeda H, Kawase K, Nishi T, Watanabe T, Takenaga K, Inozume T, Ishino T, Aki S, Lin J, Kawashima S, Nagasaki J, Ueda Y, Suzuki S, Makinoshima H, Itami M, Nakamura Y, Tatsumi Y, Suenaga Y, Morinaga T, Honobe-Tabuchi A, Ohnuma T, Kawamura T, Umeda Y, Nakamura Y, Kiniwa Y, Ichihara E, Hayashi H, Ikeda JI, Hanazawa T, Toyooka S, Mano H, Suzuki T, Osawa T, Kawazu M, Togashi Y. Immune evasion through mitochondrial transfer in the tumour microenvironment. Nature, 638:225-236, 2025

    4. Bando H, Kumagai S, Kotani D, Mishima S, Irie T, Itahashi K, Tanaka Y, Habu T, Fukaya S, Kondo M, Tsushima T, Hara H, Kadowaki S, Kato K, Chin K, Yamaguchi K, Kageyama SI, Hojo H, Nakamura M, Tachibana H, Wakabayashi M, Fukui M, Fuse N, Koyama S, Mano H, Nishikawa H, Shitara K, Yoshino T, Kojima T. Atezolizumab following definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma - a multicenter phase 2 trial (EPOC1802). Nature cancer, 6:445-459, 2025

    5. Torasawa M, Shukuya T, Uemura K, Hayashi T, Ueno T, Kohsaka S, Masui Y, Shirai Y, Okura M, Asao T, Mitsuishi Y, Shimada N, Takahashi F, Takamochi K, Suzuki K, Takahashi K, Seyama K. Lymphangioleiomyomatosis as a potent lung cancer risk factor: Insights from a Japanese large cohort study. Respirology (Carlton, Vic.), 29:815-824, 2024

    6. Kobayashi H, Okajima K, Zhang L, Hirai T, Ishibashi Y, Tsuda Y, Ikegami M, Kawai A, Tanaka S. Embryonal and alveolar rhabdomyosarcoma in adolescents/young adults, adults and older adults: a population-based cohort study. Japanese journal of clinical oncology, 54:903-910, 2024

    7. Torasawa M, Yoshida T, Shiraishi K, Goto N, Ueno T, Ichikawa H, Yagishita S, Kohsaka S, Goto Y, Yatabe Y, Hamada A, Mano H, Ohe Y. Rapid Response to Lenvatinib and Disease Flare After Discontinuation in a Patient With Thymic Carcinoma Harboring KIT Exon 11 Mutation: A Case Report. JTO clinical and research reports, 5:100657, 2024

    8. Kohsaka S, Yagishita S, Shirai Y, Matsuno Y, Ueno T, Kojima S, Ikeuchi H, Ikegami M, Kitada R, Yoshioka KI, Toshimitsu K, Tabata K, Yokoi A, Doi T, Yamamoto N, Owa T, Hamada A, Mano H. A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency. NPJ precision oncology, 8:117, 2024

    9. Yamaguchi T, Ikegami M, Aruga T, Kanemasa Y, Horiguchi SI, Kawai K, Takao M, Yamada T, Ishida H. Genomic landscape of comprehensive genomic profiling in patients with malignant solid tumors in Japan. International journal of clinical oncology, 29:1417-1431, 2024

    10. Machitani M, Nomura A, Yamashita T, Yasukawa M, Ueki S, Fujita KI, Ueno T, Yamashita A, Tanzawa Y, Watanabe M, Taniguchi T, Saitoh N, Kaneko S, Kato Y, Mano H, Masutomi K. Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity. Nature cell biology, 26:932-945, 2024

    11. Kawase K, Taguchi A, Ishizaka A, Lin J, Ueno T, Yoshimoto D, Eguchi S, Mori S, Sone K, Mori M, Yonekura S, Hanazawa T, Maeda D, Kukimoto I, Mano H, Osuga Y, Kawana K, Kawazu M. Allelic loss of HLA class I facilitates evasion from immune surveillance in cervical intraepithelial neoplasia. HLA, 103:e15509, 2024

    12. Nakata E, Osone T, Ogawa T, Taguchi T, Hattori K, Kohsaka S. Prevalence of neurotrophic tropomyosin receptor kinase (NTRK) fusion gene positivity in patients with solid tumors in Japan. Cancer medicine, 13:e7351, 2024

    13. Ikeuchi H, Matsuno Y, Kusumoto-Matsuo R, Kojima S, Ueno T, Ikegami M, Kitada R, Sumiyoshi-Okuma H, Kojima Y, Yonemori K, Yatabe Y, Takamochi K, Suzuki K, Yoshioka KI, Mano H, Kohsaka S. GLI1 confers resistance to PARP inhibitors by activating the DNA damage repair pathway. Oncogene, 43:3037-3048, 2024

    14. Kage H, Kohsaka S, Tatsuno K, Watanabe K, Shinozaki-Ushiku A, Isago H, Ushiku T, Aburatani H, Mano H, Oda K. Molecular analysis of non-small cell lung cancer using a dual-targeted DNA and RNA comprehensive genomic profiling panel. Respiratory investigation, 62:910-913, 2024

    15. Mukohara F, Iwata K, Ishino T, Inozume T, Nagasaki J, Ueda Y, Suzawa K, Ueno T, Ikeda H, Kawase K, Saeki Y, Kawashima S, Yamashita K, Kawahara Y, Nakamura Y, Honobe-Tabuchi A, Watanabe H, Dansako H, Kawamura T, Suzuki Y, Honda H, Mano H, Toyooka S, Kawazu M, Togashi Y. Somatic mutations in tumor-infiltrating lymphocytes impact on antitumor immunity. Proceedings of the National Academy of Sciences of the United States of America, 121:e2320189121, 2024

    16. Iwasawa O, Ikegami M, Miyagawa T, Morita H, Saito H, Omori I, Awaji K, Omatsu J, Yamada D, Kage H, Oda K, Sato S, Sumida H. Association of genetic alterations with prognosis in extramammary Paget disease: insights into the involvement of somatic CDKN2A variants in patients with a poor prognosis. The British journal of dermatology, 192:46-54, 2024

    17. Hirose T, Ikegami M, Kida K, Ueno T, Kitada R, Wang L, Tanaka S, Endo M, Nakashima Y, Kanomata N, Mano H, Yamauchi H, Kohsaka S. Cancer risk assessment of premalignant breast tissues from patients with BRCA mutations by genome profiling. NPJ breast cancer, 10:87, 2024

    18. Tokura M, Ando MM, Kojima Y, Kitadai R, Yazaki S, Atutubo CMN, Li RK, Perez MZ, Gorospe AE, Madrid MA, Ordinario MVC, Imasa MSB, Sudo K, Shimoi T, Suto A, Kohsaka S, Machida R, Sadachi R, Yoshida M, Yatabe Y, Hata T, Nakamura K, Yonemori K, Shiino S. Multicenter Prospective Study in HER2-Positive Early Breast Cancer for Detecting Minimal Residual Disease by Circulating Tumor DNA Analysis With Neoadjuvant Chemotherapy: HARMONY Study. Breast cancer : basic and clinical research, 18:11782234241288671, 2024

    19. Terada N, Koba H, Nanjo S, Kimura H, Nishiyama A, Yoneda T, Takeda T, Shirasaki H, Nishi K, Sone T, Yamada T, Takayama K, Shibata K, Matsuoka H, Kita T, Nagata K, Tambo Y, Ohkura N, Hara J, Kasahara K, Kohsaka S, Mano H, Yano S. EGFR-V834L combined with L858R mutation reduced afatinib sensitivity and associated to early recurrence in lung cancer. Translational lung cancer research, 13:3067-3082, 2024