Targeted Inhibition of CHD1L by OTI-611 Reprograms Chemotherapy and Targeted Therapy-Induced Cell Cycle Arrest and Suppresses Proliferation to Produce Synergistic Antitumor Effects in Breast and Colorectal Cancer

Article

作者: Zhou, Qiong ; LaBarbera, Daniel V. ; Esquer, Hector

The second and third most frequently diagnosed cancers worldwide are breast (2.3 million new cases) and colorectal (1.9 million new cases), respectively. Although advances in cancer therapies and early detection have improved the overall survival of patients, patients still develop resistance or cancer recurrence. Thus, the development of novel therapies that can affect multiple mechanisms of drug resistance and cell survival is ideal for the treatment of advanced and metastatic cancers. CHD1L is a novel oncogenic protein involved in regulating chromatin remodeling, DNA damage repair, epithelial-mesenchymal transition (EMT), and programmed cell death via PARthanatos. Herein, we assess in real-time how the CHD1L inhibitor (CHD1Li) OTI-611 modulates cell cycle progression in Colo678, SUM149PT, and SW620 cell lines. By utilizing a cell cycle reporter, we tracked the real-time cell cycle progression of cancer cells treated with OTI-611 alone and in combination with standard-of-care (SOC) therapies. Our results indicate that OTI-611 causes G1 phase cell cycle arrest through a CHD1L-mediated mechanism that regulates Cyclin D1 expression and localization. As a result of this mechanism, OTI-611 can reprogram the cell cycle effects of other antitumor agents to modulate and arrest cells in G1 when used in combination, including agents commonly known to arrest cells in the G2/M phase. Therefore, we conclude that OTI-611-induced G1 arrest represents a critical component of its unique mechanism of action, contributing significantly to its anticancer activity.

International Journal of Molecular Sciences

CHD1L Inhibitor OTI-611 Synergizes with Chemotherapy to Enhance Antitumor Efficacy and Prolong Survival in Colorectal Cancer Mouse Models

Article

作者: Awolade, Paul ; Clune, Sophia ; Esquer, Hector ; Sala, Rita ; Zhou, Qiong ; Kellett, Timothy ; Messersmith, Wells A. ; LaBarbera, Daniel V. ; Pike, Laura A.

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. It is universally treated with a combination of the DNA damaging chemotherapy drugs irinotecan, 5-Fluorouracil (5-FU), and oxaliplatin. CHD1L is a novel oncogene that plays critical roles in chromatin remodeling and DNA damage repair, as well as the regulation of malignant gene expression. We show that an inhibitor of CHD1L, OTI-611, when combined with chemotherapy significantly increases DNA damage in CRC cell lines. OTI-611 also synergizes with SN-38, 5-FU, and oxaliplatin in killing CRC tumor organoids. We also demonstrate that, as in breast cancer, OTI-611 traps CHD1L, PARP1, and PARP2 onto chromatin. The entrapment of CHD1L causes the deprotection of PAR chains in the nucleus, ultimately resulting in cell death by CHD1Li-mediated PARthanatos, as measured by AIF translocation to the nucleus. Finally, the combination of low doses of OTI-611 with irinotecan significantly reduces tumor volume and extends survival in CRC xenograft mouse models compared to irinotecan alone. The combination of standard of care chemotherapy drugs with CHD1Li represents a promising advancement in future therapeutic strategies for CRC and other cancers driven by CHD1L.

International Journal of Molecular Sciences

CHD1L Regulates Cell Survival in Breast Cancer and Its Inhibition by OTI-611 Impedes the DNA Damage Response and Induces PARthanatos

Article

作者: Zhou, Qiong ; Awolade, Paul ; LaBarbera, Daniel V. ; Esquer, Hector ; Kellett, Timothy ; Sala, Rita ; Kearns, Jeffrey T.

The Chromodomain helicase DNA-binding protein 1-like (CHD1L) is a nucleosome remodeling enzyme, which plays a key role in chromatin relaxation during the DNA damage response. Genome editing has shown that deletion of CHD1L sensitizes cells to PARPi, but the effect of its pharmacological inhibition has not been defined. Triple-negative breast cancer SUM149PT, HCC1937, and MDA-MB-231 cells were used to assess the mechanism of action of the CHD1Li OTI-611. Cytotoxicity as a single agent or in combination with standard-of-care treatments was assessed in tumor organoids. Immunofluorescence was used to assess the translocation of PAR and AIF to the cytoplasm or the nucleus and to study markers of DNA damage or apoptosis. Trapping of PARP1/2 or CHD1L onto chromatin was also assessed by in situ subcellular fractionation and immunofluorescence and validated by Western blot. We show that the inhibition of CHD1L’s ATPase activity by OTI-611 is cytotoxic to triple-negative breast cancer tumor organoids and synergizes with PARPi and chemotherapy independently of the BRCA mutation status. The inhibition of the remodeling function blocks the phosphorylation of H2AX, traps CHD1L on chromatin, and leaves PAR chains on PARP1/2 open for hydrolysis. PAR hydrolysis traps PARP1/2 at DNA damage sites and mediates PAR translocation to the cytoplasm, release of AIF from the mitochondria, and induction of PARthanatos. The targeted inhibition of CHD1L’s oncogenic function by OTI-611 signifies an innovative therapeutic strategy for breast cancer and other cancers. This approach capitalizes on CHD1L-mediated DNA repair and cell survival vulnerabilities, thereby creating synergy with standard-of-care therapies

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适应症	最高研发状态	国家/地区	公司	日期
乳腺癌	临床前	-	Onconaut Therapeutics, Inc.	2024-09-08
结直肠癌	临床前	-	Onconaut Therapeutics, Inc.	2024-09-08
三阴性乳腺癌	临床前	美国	Skaggs School of Pharmacy & Pharmaceutical Sciences	2024-08-06