Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor

Yi, Xiaofang; Gao, Ruo-Lin; Sun, Li; Wu, Zhixuan; Zhang, Shuling; Huang, Le-Tian; Han, Cheng-Bo; Ma, Jie-Tao

doi:10.1016/j.biopha.2023.114770

Cited by 4 publications

(3 citation statements)

References 184 publications

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“…PARPi have been shown to have immunostimulating mechanisms, including activation of the cGAS/STING pathway in cancer cells ( 47 , 48 ). TTFields were also shown to induce immunogenic cell death and cGAS/STING activation in preclinical models and in the clinic ( 30 , 49 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

Berckmans,

Ene,

Ben-Meir

et al. 2024

Front. Oncol.

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BackgroundOvarian cancer is the leading cause of mortality among gynecological malignancies. Carboplatin and poly (ADP-ribose) polymerase inhibitors (PARPi) are often implemented in the treatment of ovarian cancer. Homologous recombination deficient (HRD) tumors demonstrate increased sensitivity to these treatments; however, many ovarian cancer patients are homologous recombination proficient (HRP). TTFields are non-invasive electric fields that induce an HRD-like phenotype in various cancer types. The current study aimed to investigate the impact of TTFields applied together with carboplatin or PARPi (olaparib or niraparib) in preclinical ovarian cancer models.MethodsA2780 (HRP), OVCAR3 (HRD), and A2780cis (platinum-resistant) human ovarian cancer cells were treated in vitro with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or with various drug concentrations. Treated cells were measured for cell count, colony formation, apoptosis, DNA damage, expression of DNA repair proteins, and cell cycle. In vivo, ID8-fLuc (HRP) ovarian cancer cells were inoculated intraperitoneally to C57BL/6 mice, which were then treated with either sham, TTFields (200 kHz), olaparib (50 mg/kg), or TTFields plus olaparib; over a period of four weeks. Tumor growth was analyzed using bioluminescent imaging at treatment cessation; and survival analysis was performed.ResultsThe nature of TTFields-drug interaction was dependent on the drug’s underlying mechanism of action and on the genetic background of the cells, with synergistic interactions between TTFields and carboplatin or PARPi seen in HRP and resistant cells. Treated cells demonstrated elevated levels of DNA damage, accompanied by G2/M arrest, and induction of an HRD-like phenotype. In the tumor-bearing mice, TTFields and olaparib co-treatment resulted in reduced tumor volume and a survival benefit relative to olaparib monotherapy and to control.ConclusionBy inducing an HRD-like phenotype, TTFields sensitize HRP and resistant ovarian cancer cells to treatment with carboplatin or PARPi, potentially mitigating a-priori and de novo drug resistance, a major limitation in ovarian cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

Berckmans,

Ene,

Ben-Meir

et al. 2024

Front. Oncol.

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“…In this condition-dependent SL interaction, genetic factors alone may not necessarily result in a synthetic lethal effect. [166][167][168] For example, some SL-based therapies have modest effects on viability in cell culture in vitro, but exhibit antiproliferative activity in mouse and zebrafish models. Among these external factors, TEM, which includes other immune cells, hormones, nutrients, hypoxia, high ROS, pH, and osmolality, may influence the strength of synthetic lethal therapeutic effects.…”

Section: The Dynamic Of Slis Beyond Tumor Cellsmentioning

confidence: 99%

“…In addition to the genetic background mentioned above, certain external conditions, such as the heterogeneity of the tumor cells, the microenvironment, and other external interferences, are required to eventually realize SL. In this condition‐dependent SL interaction, genetic factors alone may not necessarily result in a synthetic lethal effect 166–168 . For example, some SL‐based therapies have modest effects on viability in cell culture in vitro, but exhibit antiproliferative activity in mouse and zebrafish models.…”

Section: The Dynamic Of Slis Beyond Tumor Cellsmentioning

confidence: 99%

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

Ge,

Luo,

et al. 2024

MedComm – Oncology

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Synthetic lethality (SL), a genetic concept, has revolutionized the development of antitumor therapies by providing avenues to target previously “undruggable” targets with enhanced specificity for tumor cells over normal tissue. The principles of SL have expanded beyond genetic definitions to encompass biological functions, including genome stability, cell cycle regulation, cell death mechanisms, cellular metabolism, cell–cell interactions, and the tumor microenvironment (TME). Tumor cells with inactivated survival pathways are sensitive to therapeutic inhibition of compensatory mechanisms, while normal cells remain unaffected. Exploiting SL based on functional contexts has the potential to significantly improve cancer patient survival by reducing resistance to targeted therapies and enhancing antitumor efficacy when combined with other treatment modalities. This review explores the underlying mechanisms of synthetic lethality interactions (SLI) characterized by biological functions in individual cancer cells and the TME. We also provide a comprehensive summary of strategies for leveraging the dynamic nature of SLI to overcome therapeutic resistance. Additionally, we discuss various approaches and models for screening and designing potent SL agents tailored to the specific needs of cancer patients, as well as strategies for combining SL drugs in tumor treatment. This review offers valuable insights into harnessing SL as a promising avenue for precision cancer therapy.

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Impact of Drp1-regulated changes in T cell activity on the combined antitumor effects of PARPi and PD-1 inhibitors

Ma,

Song,

et al. 2024

International Immunopharmacology

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Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor

Cited by 4 publications

References 184 publications

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

Tumor Treating Fields (TTFields) induce homologous recombination deficiency in ovarian cancer cells, thus mitigating drug resistance

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

Impact of Drp1-regulated changes in T cell activity on the combined antitumor effects of PARPi and PD-1 inhibitors

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