LRRK2 inhibition potentiates PARP inhibitor cytotoxicity through inhibiting homologous recombination‐mediated DNA double strand break repair

Chen, Lifeng; Hou, Jing; Zeng, Xiangyu; Guo, Qiang; Deng, Min; Kloeber, Jake A.; Tu, Xinyi; Zhao, Fei; Wu, Zheming; Huang, Jinzhou; Luo, Kuntian; Kim, Wootae; Lou, Zhenkun

doi:10.1002/ctm2.341

Cited by 8 publications

(8 citation statements)

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“…A specific LRRK2 rs10878441 CC genotype has been linked to a poorer prognosis in Chinese breast cancer patients [ 43 ]. High LRRK2 expression has also been associated with poorer survival in ovarian cancer [ 44 ]. It was also demonstrated that inhibiting LRRK2 promoted toxicity of PARP inhibitor by reducing homologous recombination-mediated DNA double strand break repair [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…High LRRK2 expression has also been associated with poorer survival in ovarian cancer [ 44 ]. It was also demonstrated that inhibiting LRRK2 promoted toxicity of PARP inhibitor by reducing homologous recombination-mediated DNA double strand break repair [ 44 ]. LRRK2 is also involved in the ATM-Mdm2-p53 pathway that regulates cell proliferation in response to DNA damage [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Cancer Risks In Lrrk2-g2019s Pd Carriersmentioning

confidence: 99%

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Parkinson’s disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender

Lee

Saffari

et al. 2022

Aging

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Purpose: The relationship between Parkinson’s disease (PD) and cancer has been debated. Gender and genetic influences on cancer development in PD is unclear. Methods: Using QUOROM guidelines, we conducted a systematic review and meta-analysis on potential clinical and genetic factors influencing the PD and subsequent cancer relationship. English articles published in PubMed, Web of Science, and SCOPUS from 2010 to 30 August 2020 were considered for suitability. Results: Of 46 studies identified, fourteen satisfied the inclusion criteria and were further analysed. Unadjusted risk ratios (RR) and 95% confidence intervals were computed to determine the PD and cancer relationship. PD patients have decreased subsequent cancer risks (RR = 0.87, 95% CI = 0.81–0.93), reduced risks of colon, rectal, and colorectal cancer (RR = 0.77, 95% CI = 0.63–0.94), lung cancer (RR = 0.62, 95% CI = 0.48–0.80), and increased brain cancer (R = 1.48, 95% CI = 1.02–2.13) and melanoma risk (R = 1.76, 95% CI = 1.23–2.50). Compared to idiopathic PD, LRRK2-G2019S carriers had increased general cancer risks (RR = 1.26, 95% CI = 1.09–1.46), particularly brain (RR = 2.41, 95% CI = 1.06–5.50), breast (RR = 2.57, 95% CI = 1.19–5.58), colon (RR = 1.83, 95% CI = 1.13–2.99), and haematological cancers (RR = 2.05, 95% CI = 1.07–3.92). Female PD patients have decreased general cancer risks compared to male PD patients in this analysis (RR = 0.83, 95% CI = 0.69–0.98). Conclusion: PD patients have reduced risks of colon, rectal, colorectal cancer and lung cancers and increased risks of brain cancer and melanoma. LRRK2-G2019S carriers have increased cancer risks, particularly brain, breast, colon and blood cancers. Female gender was associated with reduced risks. The role of ethnicity, comorbidities, and lifestyle habits on PD patients’ subsequent cancer risk should be further investigated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Parkinson’s disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender

Lee

Saffari

et al. 2022

Aging

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“…Tissue microarrays contained 128 ovarian cancers with clinical characteristics were purchased from Alenabio and Shanghai Outdo Biotech Company. Immunohistochemical (IHC) staining was carried out as previously described ( Chen et al, 2021 ). All samples were scored by three independent pathologists.…”

Section: Methodsmentioning

confidence: 99%

An Analysis Regarding the Prognostic Significance of MAVS and Its Underlying Biological Mechanism in Ovarian Cancer

Chen

Hou

You

et al. 2021

Front. Cell Dev. Biol.

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The present study evaluates the value of mitochondrial antiviral signaling (MAVS) expression as a potential diagnostic biomarker and therapeutic target for ovarian cancer (OC) and analyses the underlying biological mechanism in this pathology. First, the association between MAVS expression determined by immunohistochemical (IHC) and clinical characteristics was systematically investigated. Overexpression of MAVS was associated with advanced clinical factors and poor survival of OC patients. Second, bioinformatics analyses, namely, gene expression, mutation analysis, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and weighted gene co-expression network analysis (WGCNA), were performed to evaluate the potential biological functions of MAVS in OC. The results showed that MAVS may play a critical role in immune cell infiltration. CIBERSORT was applied to assess the infiltration of immune cells in OC. CD8+ T cells, γδT cells, and eosinophils had significantly negative correlations with MAVS expression. Finally, sensitivity analysis found that patients with high MAVS expression were predicted to be significantly less responsive to cisplatin and paclitaxel. In conclusion, these findings suggested that MAVS influences biological behavior by regulating the immune response and that it can be used as a predictive marker for poor prognosis in OC.

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“…LRRK2 inhibitors decreased the production of tumor necrosis factor‐α by dextran sulfate sodium‐induced colitis in a mouse model and in dendritic cells from patients with Crohn's disease 6,7 . LRRK2 inhibition or depletion sensitized ovarian cancer cells with high expression of LRRK2 to poly (ADP‐ribose) polymerase (PARP) inhibitors, including olaparib, indicating that a combination therapy with LRRK2 and PARP inhibitors could be a promising therapeutic strategy to overcome resistance to PARP inhibitors in ovarian cancer 8 . Therefore, LRRK2 inhibitors have received considerable attention as therapeutic targets.…”

Section: Figurementioning

confidence: 99%

Discovery of novel thienopyrimidine derivatives as LRRK2 inhibitors

Choi

Park

Jang

et al. 2021

Bulletin Korean Chem Soc

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Leucine‐rich repeat kinase 2 (LRRK2) is considered a promising therapeutic target for Parkinson's disease, Crohn's disease, and cancer. Despite considerable research, none of these inhibitors are available for clinical application. Herein, we designed and synthesized novel thienopyrimidine derivatives by a bioisosteric replacement and investigated their structure–activity relationships. Thieno[3,2‐d]pyrimidine derivative 22 showed the most potent inhibitory activity and inhibited both wild‐type and G2019S mutant LRRK2 with IC50 values of 30 and 14 nM, respectively.

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LRRK2 inhibition potentiates PARP inhibitor cytotoxicity through inhibiting homologous recombination‐mediated DNA double strand break repair

Abstract: LRRK2 inhibitor GSK2578215A suppresses HR and sensitizes ovarian cancer cells to PARP inhibitor. LRRK2 inhibition impedes the recruitment of RAD51 by disrupting the interaction of RAD51 and BRCA2. High expression of LRRK2 is associated with poor survival of ovarian cancer patients.

Cited by 8 publications

References 36 publications

Parkinson’s disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender

Parkinson’s disease and cancer: a systematic review and meta-analysis on the influence of lifestyle habits, genetic variants, and gender

An Analysis Regarding the Prognostic Significance of MAVS and Its Underlying Biological Mechanism in Ovarian Cancer

Discovery of novel thienopyrimidine derivatives as LRRK2 inhibitors

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