Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effects

May 17, 2025EBioMedicine

Disrupting the body’s daily clock with PARP inhibitors is linked to treatment side effects in ovarian cancer patients

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Abstract

Disruptions in circadian rhythms were observed in the expression of core clock genes following treatment with rucaparib in 42 patients.

Significant changes in the expression of core clock genes BMAL1 and PER2 were found after rucaparib treatment.
These disruptions correlated with the occurrence and severity of side effects such as nausea and fatigue.
Distinct patterns of gene expression allowed for the differentiation of rucaparib-treated patients from those receiving placebo.
Rucaparib therapy also affected the expression of clock-controlled genes, including SIRT1, BRCA1, BRCA2, and TP53.
Individual variations in circadian rhythms may lead to different toxicity profiles over a 24-hour period.

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BACKGROUND: Ovarian cancer is among the most lethal malignancies in women. The advent of PARP inhibitors (PARPi) has improved outcomes. However, treatment-related toxicity remains a critical challenge, impacting patient quality of life and treatment adherence.

METHODS: In a circadian sub-study of the MAMOC trial-a double-blind, phase III study-42 patients (FIGO stage IIIA-IV) were randomised in a 2:1 ratio to receive rucaparib or placebo. In a subset of these patients, we performed differential gene expression and rhythmicity analysis on up to 800 genes, including clock and clock-controlled genes. Machine learning algorithms and mathematical modelling were employed to simulate patient-specific toxicity profiles and to explore correlations between gene expression patterns and treatment-related side effects.

FINDINGS: Our analysis revealed significant disruptions in circadian rhythms, specifically in the expression of the core clock genes BMAL1 and PER2, following treatment. These disruptions strongly correlated with the severity and frequency of side effects, including nausea and fatigue, displaying opposite trends between the placebo and rucaparib-treated groups. K-means clustering successfully distinguished rucaparib-treated patients from those receiving placebo based on BMAL1 phase and gene expression profiles. In addition, rucaparib therapy also altered the expression of several clock-controlled genes, including SIRT1, BRCA1, BRCA2, and TP53. Notably, our data suggest that individual differences in circadian rhythms may lead to distinct 24-h toxicity profiles among patients.

INTERPRETATION: These findings suggest that circadian rhythm dysregulation may contribute to the toxicity of PARPi therapy. Aligning treatment timing with circadian rhythms could mitigate these adverse effects, and improve patient outcomes.

FUNDING: This study was funded by the Dr. Rolf Schwiete Stiftung and the MSH Medical School Hamburg, Germany. The MAMOC trial (ClinicalTrials.gov: NCT04227522) was funded by Clovis Oncology, United States.

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Circadian rhythm disruption by PARP inhibitors correlates with treatment toxicity in patients with ovarian cancer and is a predictor of side effects

Abstract

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