Paclitaxel sensitizes homologous recombination-proficient ovarian cancer cells to PARP inhibitor via the CDK1/BRCA1 pathway

Yanaihara, Nozomu; Yoshino, Yuki; Noguchi, Daito; Tabata, Junya; Takenaka, Masataka; Iida, Yasushi; Saito, Misato; Yanagida, Satoshi; Iwamoto, Masami; Kiyokawa, Takako; Chiba, Natsuko; Okamoto, Aikou

doi:10.1016/j.ygyno.2022.11.006

Cited by 11 publications

(8 citation statements)

References 21 publications

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“…Our results indicate that CDK1 is the pivotal point for all our tested PARPi in ovarian cancer due to all the upstream pathways that causally contribute to resistance through it. This is supported by the observation that CDK1 depletion after paclitaxel treatment in combination with PARP inhibition significantly reduces cell growth of HR-proficient ovarian cancer cells (Yanaihara et al ., 2023). Here a pivotal point refers to a gene that is involved in several of the pathways from the top 10 genes that drive PARPi resistance - for example, CDK1 is downstream of all seven G2/M cell cycle genes driving Niraparib resistance in NSCLC (Figure 3).…”

Section: Resultsmentioning

confidence: 72%

“…We also observe this effect for CDK1 in NSCLC (Figure 4C). This is an unexpected finding which can partially be explained by the observation that CDK1 plays a role in both the G2/M cell cycle phase and in HR and is known to contribute to resistance or sensitize cancer cells to DNA damage-causing agents depending on the interaction of these two pathways (Sunada et al, 2021). Inclusion of CDK1's effect on HR in follow-up analyses could provide insight on why this differential effect is observed in NSCLC for olaparib and talazoparib, as WEE1 affects sensitivity to these compounds through CDK1.…”

Section: Signaling Pathway Evaluation Of Parp Inhibitors Such As Nira...mentioning

confidence: 99%

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Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference

Truter,

Bergh,

van den Heever

et al. 2024

Preprint

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Introduction: There are many cancer drugs in development which target the DNA damage response (DDR), following early successes of drugs such as olaparib. However, various challenges to the success of these inhibitors exist, including the emergence of resistance, the identification of appropriate biomarkers to identify patients who will respond to treatment, as well as the identification of combination therapies that improve efficacy without a concomitant increase in toxicity. While the identification of biomarkers of resistance could aid in overcoming these challenges, current methods mostly generate lists of potential genes, proteins that display changes in cancer patients, without exposing the underlying, and often critical, mechanisms of resistance. Methods: We have developed the Adaptable Large-Scale Causal Analysis (ALaSCA) software platform, which applies Pearlian Causal Inference (PCI) techniques to specifically transcriptomic, proteomic and phenotypic multi-omics data. ALaSCA quantifies the causal contributions of different biological pathways to an outcome such as responsiveness to treatment. The strength of applying PCI to biological pathways lies in quantifying the causal contributions of targets, through their related pathways, to drug sensitivity - as opposed to merely enriching or grouping lists of genes into pathways. We applied ALaSCA to transcriptomic data for several different compounds related to three known inhibitor types that target DDR proteins: an ATR, a CDK7, and several PARP inhibitors. Our aim was to use causal methods to evaluate biological signaling pathways to identify resistance mechanisms that can be used for patient stratification and development of combination therapies in breast, ovarian and non-small cell lung cancer (NSCLC). Key findings: We observed that niraparib seems to have a different resistance mechanism than other PARP inhibitors in breast and NSCLC, which is driven by CDK1 as opposed to base excision or nucleotide excision repair. Additionally, CDK7 appears to be a significant driver of PARP inhibitor resistance, especially for niraparib, through predominantly the G2/M cell cycle phase and to a lesser extent nucleotide excision repair in breast and ovarian cancer, but not in NSCLC. Lastly, we identified that genes from the homologous recombination pathway drive resistance to AZD6738, an ATR inhibitor, in breast cancer, and that AZD6738 and irinotecan have differing resistance mechanisms in ovarian cancer, indicating the potential of combining these treatments. Next steps: Our findings demonstrate the potential of ALaSCA to generate interesting insights for treatments when applied to public data and well-known inhibitors. Partnership with industry drug discovery groups using proprietary data to rerun the above evaluations will further refine and confirm these findings.

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Section: Resultsmentioning

confidence: 72%

Section: Signaling Pathway Evaluation Of Parp Inhibitors Such As Nira...mentioning

confidence: 99%

Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference

Truter,

Bergh,

van den Heever

et al. 2024

Preprint

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“…Extensive subsequent studies have focused on expanding the use of these inhibitors to patients. A recent study showed that paclitaxel inhibits CDK1, resulting in weakened BRCA1 phosphorylation, which sensitizes ovarian cancer cells with proficient homologous recombination to PARP inhibitors [24] . Lu et al .…”

Section: Introductionmentioning

confidence: 99%

Abrogation of KLF5 sensitizes <italic>BRCA1</italic>-proficient pancreatic cancer to PARP inhibition

Zhang,

Liu,

et al. 2024

ABBS

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Poly ADP-ribose polymerase (PARP) inhibitor monotherapies are selectively effective in patients with pancreatic, breast, prostate, and ovarian cancers with BRCA1 mutations. Cancer patients with more frequent wild-type BRCA show poor responses to PARP inhibitors. Moreover, patients who are initially sensitive to these inhibitors eventually respond poorly to drugs. In the present study, we discover that abrogation of Kruppel-like factor 5 (KLF5) significantly inhibits homologous recombination, which is the main mechanism for DNA double-stranded repair. Furthermore, the downregulation of KLF5 expression promotes the DNA damage induced by olaparib and significantly reduces the IC 50 of the RARP inhibitor in pancreatic cancer cells. Overexpression of BRCA1 reverses the above effects caused by silencing of KLF5 . Olaparib combined with a KLF5 inhibitor has an enhanced cytotoxic effect. Mechanistically, we identify BRCA1 as a KLF5 target gene. BRCA1 is positively correlated with KLF5 in PDAC tissue. Our results indicate that inhibition of KLF5 may induce BRCAness in a larger pancreatic cancer subset with proficient BRCA. The combination of KLF5 inhibitors and PARP inhibitors provides a novel treatment strategy to enhance the sensitivity of BRCA1-proficient pancreatic cancer to PARP inhibitors.

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“…Recently, some genes and chemical agents that have not been considered to directly act on HR have been reported to affect HR activity. For example, inhibition of TTK protein kinase, which plays an important role in regulating spindle assembly checkpoint signaling, impaired HR in basal-like breast cancer cells ( 21 ), and a chemothrerapeutic agent paclitaxel, which exert its cytotoxic effect by arresting mitosis through microtubule stabilization, decease HR activity in HR-proficient (HRP) EOC cells ( 22 ). Thus, antiangiogenic agents may affect HR activity in EOC cells, which improves the sensitivity of these cells to PARPi.…”

Section: Introductionmentioning

confidence: 99%

Bevacizumab increases the sensitivity of olaparib to homologous recombination-proficient ovarian cancer by suppressing CRY1 via PI3K/AKT pathway

Iida,

Yanaihara,

Yoshino

et al. 2024

Front. Oncol.

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PARP inhibitors have changed the management of advanced high-grade epithelial ovarian cancer (EOC), especially homologous recombinant (HR)-deficient advanced high-grade EOC. However, the effect of PARP inhibitors on HR-proficient (HRP) EOC is limited. Thus, new therapeutic strategy for HRP EOC is desired. In recent clinical study, the combination of PARP inhibitors with anti-angiogenic agents improved therapeutic efficacy, even in HRP cases. These data suggested that anti-angiogenic agents might potentiate the response to PARP inhibitors in EOC cells. Here, we demonstrated that anti-angiogenic agents, bevacizumab and cediranib, increased the sensitivity of olaparib in HRP EOC cells by suppressing HR activity. Most of the γ-H2AX foci were co-localized with RAD51 foci in control cells. However, most of the RAD51 were decreased in the bevacizumab-treated cells. RNA sequencing showed that bevacizumab decreased the expression of CRY1 under DNA damage stress. CRY1 is one of the transcriptional coregulators associated with circadian rhythm and has recently been reported to regulate the expression of genes required for HR in cancer cells. We found that the anti-angiogenic agents suppressed the increase of CRY1 expression by inhibiting VEGF/VEGFR/PI3K pathway. The suppression of CRY1 expression resulted in decrease of HR activity. In addition, CRY1 inhibition also sensitized EOC cells to olaparib. These data suggested that anti-angiogenic agents and CRY1 inhibitors will be the promising candidate in the combination therapy with PARP inhibitors in HR-proficient EOC.

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Paclitaxel sensitizes homologous recombination-proficient ovarian cancer cells to PARP inhibitor via the CDK1/BRCA1 pathway

Cited by 11 publications

References 21 publications

Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference

Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference

Abrogation of KLF5 sensitizes <italic>BRCA1</italic>-proficient pancreatic cancer to PARP inhibition

Bevacizumab increases the sensitivity of olaparib to homologous recombination-proficient ovarian cancer by suppressing CRY1 via PI3K/AKT pathway

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Paclitaxel sensitizes homologous recombination-proficient ovarian cancer cells to PARP inhibitor via the CDK1/BRCA1 pathway

Cited by 11 publications

References 21 publications

Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference

Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference

Abrogation of KLF5 sensitizes &lt;italic&gt;BRCA1&lt;/italic&gt;-proficient pancreatic cancer to PARP inhibition

Bevacizumab increases the sensitivity of olaparib to homologous recombination-proficient ovarian cancer by suppressing CRY1 via PI3K/AKT pathway

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Abrogation of KLF5 sensitizes <italic>BRCA1</italic>-proficient pancreatic cancer to PARP inhibition