Annual Report 2023
Laboratory of Genome Stress Signaling
Bunsyo Shiotani
Introduction
Cancer-related genomic abnormalities are caused by environmental, genetic and DNA replication factors. These factors induce obstacles to genomic DNA replication, resulting in DNA replication stress during DNA replication. DNA replication stress resistance mechanisms that respond to DNA replication stress allow DNA replication to continue and complete, but may cause the acquisition of genomic instability and promote cancer development. We focus on the cell survival strategy through DNA replication stress tolerance, and work on the mechanism underlying genomic instability, the associated mechanisms of cancer development and drug resistance, and the development of new therapies based on these mechanisms.
The Team and What We Do
Our group is focusing on the DNA replication stress response and cellular response to tolerate DNA replication stress, as well as the associated mechanisms of the cancer development and acquisition of drug resistance. Based on these mechanisms, novel cancer prevention and therapeutic strategy will be developed.
Research Activities
1) In the lung adenocarcinoma model, we showed that KRASG12V expression induces heterochromatin-associated DNA replication stress. An ATR-PrimPol-regulated repriming tolerates DNA replication stress and promotes genomic instability followed by cell transformation. The study also showed that high expression of ATR in KRAS-mutant cancer patients is associated with poor prognosis. The results of this study are expected to lead to the elucidation of novel pathologies in lung adenocarcinoma and the establishment of new therapeutic strategies by targeting the DNA replication stress tolerance mechanism.
2) In SWI/SNF complex-deficient cells, especially SMARCA4-deficient cells, we found that the combination of ATRi and PARPi has a strong synergistic effect. PARP inhibition enhances cell dependence on ATRi by increasing heterochromatin and enhancing DNA replication stress. SMARCA4-deficient cancer cells showed stronger DNA damage in response to combined ATRi and PARPi treatment. In vivo experiments confirmed the efficacy of this combination therapy in a SMARCA4-deficient lung adenocarcinoma xenograft model. These results suggest a novel mechanism by which PARPi-induced heterochromatin-associated DNA replication stress enhances ATRi susceptibility, providing a potential rationale for therapeutic strategies targeting SMARCA4-deficient tumors.
3) The mechanism of osimertinib resistance, a molecularly targeted drug that targets EGFR mutations, was analysed. The results showed that osimertinib treatment induces abnormal DNA replication and genomic aberrations, which may promote the acquisition of resistance and contribute to cancer recurrence.
4) We screened for factors whose phosphorylation levels are increased under DNA replication stress induced by KRASG12V expression. We showed that HMGA1 is a factor that negatively regulates replication rate depending on its expression and phosphorylation status. Furthermore, a phosphorylation site mutant of HMGA1 increased DNA damage levels and suppressed cell proliferation, suggesting that HMGA1 is a factor that appropriately regulates DNA replication and maintains genome stability in response to genomic damage.
Education
We provided research guidance to one postdoctoral fellow, and 6 trainees from Hoshi University, Kitasato University, Tokyo Medical and Dental University, and Keio University.
Future Prospects
DNA replication stress tolerance is a driving force for genome instability during cancer development and malignant transformation. We aim to elucidate the mechanism by which DNA replication stress tolerance promotes genomic instability and carcinogenesis, and to develop novel cancer prevention strategies and cancer therapies by modulating DNA replication stress tolerance.
List of papers published in 2023
Journal
1. Igarashi T, Mazevet M, Yasuhara T, Yano K, Mochizuki A, Nishino M, Yoshida T, Yoshida Y, Takamatsu N, Yoshimi A, Shiraishi K, Horinouchi H, Kohno T, Hamamoto R, Adachi J, Zou L, Shiotani B. An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress. Nature communications, 14:4991, 2023
2. Yano K, Shiotani B. Emerging strategies for cancer therapy by ATR inhibitors. Cancer science, 114:2709-2721, 2023
3. Uchida C, Niida H, Sakai S, Iijima K, Kitagawa K, Ohhata T, Shiotani B, Kitagawa M. p130RB2 positively contributes to ATR activation in response to replication stress via the RPA32-ETAA1 axis. Biochimica et biophysica acta. Molecular cell research, 1870:119484, 2023