CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors.

Abstract

BACKGROUND:

High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.

EXPERIMENTAL DESIGN:

We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.

RESULTS:

We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.

CONCLUSION:

Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

• Authors: Xue Lu, Yaowu He, Rebecca L Johnston, Devathri Nanayakarra, Sivanandhini Sankarasubramanian, J Alejandro Lopez, Michael Friedlander, Murugan Kalimutho, John D Hooper, Prahlad V Raninga, Kum Kum Khanna
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 41 Issue 1 Pg. 355 (Dec 21 2022) ISSN: 1756-9966 [Electronic] England
• PMID: 36539830 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Poly(ADP-ribose) Polymerase Inhibitors
• CBLC137
• SSRP1 protein, human
• DNA-Binding Proteins
• High Mobility Group Proteins
• Transcriptional Elongation Factors

Topics

• Female
• Humans
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)
• Recombinational DNA Repair
• Ovarian Neoplasms (drug therapy, genetics, pathology)
• Carcinoma, Ovarian Epithelial (drug therapy)
• Cell Line, Tumor
• DNA-Binding Proteins (genetics)
• High Mobility Group Proteins (metabolism)
• Transcriptional Elongation Factors (genetics)