Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints

Kong, Yi Wen; Dreaden, Erik C.; Morandell, Sandra; Zhou, Wen; Dhara, Sanjeev; Sriram, Ganapathy; Lam, Fred C.; Patterson, Jesse C.; Quadir, Mohiuddin; Dinh, Anh T.; Shopsowitz, Kevin E.; Varmeh, Shohreh; Yılmaz, Ömer H.; Lippard, Stephen J.; Reinhardt, Hans Christian; Hemann, Michael T.; Hammond, Paula T.; Yaffe, Michael B.

doi:10.1038/s41467-020-17958-z

Cited by 28 publications

(22 citation statements)

References 59 publications

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“…The treatment of triple-negative breast cancer (TNBC) containing mutant p53 with the pan-CDK inhibitor roscovitine followed by doxorubicin has led to increased overall survival of mice with implanted TNBC tumors [ 109 ]. Deletion of the DNA repair protein XPA in lung adenocarcinomas enhances the synthetic lethality between cell cycle kinase MK2 inhibitors and cisplatin in cells with mutant p53 [ 110 ]. Interestingly, inhibition of the G2 kinase WEE1 using the specific drug AZD1775 enhances carboplatin efficacy in ovarian cancer cells with mutant p53 and in phase II trial patients with ovarian cancer [ 111 ].…”

Section: Studies On the Interactions Of Dna Repair Telomere Homeomentioning

confidence: 99%

The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Vodička

Anděra

Opattová

et al. 2021

Cancers

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The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy.

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Section: Studies On the Interactions Of Dna Repair Telomere Homeomentioning

confidence: 99%

The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Vodička

Anděra

Opattová

et al. 2021

Cancers

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“…In addition to telomere homolog oligonucleotides, other oligonucleotide therapeutics based on antisense RNAs and small interfering RNA (siRNA) modify the mRNA metabolism [282]. Using siRNA against repair protein XPA (NER) and co-targeting the synthetic lethal relationship with the cell cycle checkpoints, kinase MK2 enhances the antitumor response in P53-deficient cancers [283]. In myeloma, ILF2 antisense oligonucleotide (Interleukin Enhancer Binding Factor, a key modulator of the DNA repair pathway) is a synthetic lethal target with DNA2 (DNA replication helicase/nuclease 2) [284].…”

Section: Other Oligonucleotides or Small Interfering Rnamentioning

confidence: 99%

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Molinaro

Martoriati

Cailliau

2021

Cancers

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Cells respond to genotoxic stress through a series of complex protein pathways called DNA damage response (DDR). These monitoring mechanisms ensure the maintenance and the transfer of a correct genome to daughter cells through a selection of DNA repair, cell cycle regulation, and programmed cell death processes. Canonical or non-canonical DDRs are highly organized and controlled to play crucial roles in genome stability and diversity. When altered or mutated, the proteins in these complex networks lead to many diseases that share common features, and to tumor formation. In recent years, technological advances have made it possible to benefit from the principles and mechanisms of DDR to target and eliminate cancer cells. These new types of treatments are adapted to the different types of tumor sensitivity and could benefit from a combination of therapies to ensure maximal efficiency.

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“…In addition, CENPK's positive regulation of β-catenin expression and nuclear translocation could contribute to the activation of Wnt signaling, which was consistent with previous reports [33,34] . Nucleotide excision repair is the principal DNA damage repair mechanism in cancer cells with platinum treatment [35] , and p53 is a key regulator in nucleotide excision repair that mediates cancer cell resistance to platinum [36] . Wnt signaling could also facilitate cancer cell resistance to platinum through other mechanisms, including regulation of cancer stemness, EMT, and DNA damage repair [16,37] .…”

Section: Discussionmentioning

confidence: 99%

CENPK Interacts with SOX6 to Promote Cervical Cancer Stemness and Chemoresistance Through Wnt and P53 Signaling

Lin

Wang

Liu

et al. 2021

Preprint

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Background Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. It is meaningful to develop alternative targets for eliminating cancer stem cells (CSCs) properties, suppressing metastasis, and alleviating chemoresistance in cervical cancer. This study clarifies the role of CENPK in cervical cancer stemness and chemoresistance and its clinical significance in cancer progression. Methods Human cervical cancer cell lines, xenografts, and clinical samples were used for expression and functional analysis. CENPK expression in cervical cancer was analyzed by bioinformatics based on a microarray and TCGA database and immunohistochemistry based on 119 paraffin-embedded cervical cancer specimens and 35 paraffin-embedded adjacent normal tissues in a tissue chip. Results CENPK served as an oncogene by promoting CSCs properties, DNA damage repair, epithelial-mesenchymal transition and DNA replication, thus inducing cisplatin/carboplatin resistance, cell metastasis and proliferation in cervical cancer. Intriguingly, targeting CENPK markedly prolonged the survival time of cervical cancer-bearing mice, and improved chemotherapy sensitivity of cervical cancer cells in vivo. CENPK also interacted with tumor suppressor gene SOX6 to activate Wnt signaling and inactivate p53 signaling. CENPK modulated expression of key regulators in CSCs properties, DNA damage repair, epithelial-mesenchymal transition and DNA replication by disrupting SOX6-β-catenin interaction, promoting β-catenin expression and nuclear translocation, and facilitating SOX6-mediated p53 ubiquitination and nuclear export, thus stimulating cervical cancer stemness, chemoresistance, metastasis and proliferation by. Interestingly, the RAD21/SMC3 complex, downstream targets of β-catenin, enhanced CENPK transcription to form a positive regulatory circuit through Wnt signaling. Facilitation of Wnt signaling by iRhom2 further activated the CENPK/SOX6-β-catenin-RAD21/SMC3 loop and conferred cervical cancer progression, suggesting a Wnt-p53 pathway crosstalk. Importantly, CENPK was upregulated in cervical cancer, correlated with cancer recurrence, and independently predicted poor patient prognosis. Conclusions This work identifies CENPK as a prognostic indicator and highlights targeting of CENPK as a novel strategy in the treatment of cervical cancer.

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Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints

Cited by 28 publications

References 59 publications

The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction

Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

CENPK Interacts with SOX6 to Promote Cervical Cancer Stemness and Chemoresistance Through Wnt and P53 Signaling

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