Combinations of ATR, Chk1 and Wee1 Inhibitors with Olaparib Are Active in Olaparib Resistant Brca1 Proficient and...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Poly(ADP-ribose) polymerases inhibitors (PARPi) are effective in ovarian cancer, particularly for tumors with homologous recombination (HR) repair defects like BRCA1/2 mutations.
• However, resistance to PARPi is a significant clinical challenge, developing via diverse molecular mechanisms.

Purpose of the Study:

• To generate and characterize olaparib-resistant ovarian cancer cell lines (ID8 F3 and ID8 Brca1-/-).
• To elucidate the molecular mechanisms underlying olaparib resistance in both HR-proficient and HR-deficient contexts.
• To evaluate the synergistic potential of combining olaparib with ATR, Chk1, and Wee1 inhibitors.

Main Methods:

• Olaparib-resistant ID8 F3 (HR proficient) and ID8 Brca1-/- (HR deficient) murine ovarian cells were developed using stepwise in vitro drug selection.
• Pharmacological characterization and molecular analyses were performed on both sensitive and resistant cell lines.

Main Results:

• In HR-proficient cells, olaparib resistance was primarily attributed to multidrug resistance 1 (MDR1) gene overexpression.
• In HR-deficient cells, resistance involved multiple mechanisms including MDR1 overexpression, reduced PARP1 levels, and partial HR repair reactivation.
• Combinations of olaparib with ATR, Chk1, and Wee1 inhibitors demonstrated synergistic activity in both sensitive and resistant cell lines, irrespective of HR status.

Conclusions:

• Generated olaparib-resistant cell lines exhibit varied resistance mechanisms, providing a valuable model for studying resistance.
• These findings highlight the potential of combining PARPi with ATR, Chk1, and Wee1 inhibitors as a therapeutic strategy for PARPi-resistant ovarian cancers.