Sensitization of colorectal cancer to irinotecan therapy by PARP inhibitor rucaparib

Augustine, Titto; Maitra, Radhashree; Zhang, Jinghang; Nayak, Jay; Goel, Sanjay

doi:10.1007/s10637-018-00717-9

Cited by 34 publications

(30 citation statements)

References 55 publications

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“…This is somewhat in contrast to the efficacy of PARP inhibitors seen in ovarian cancer, in which TP53 is almost invariably mutated [44] . However, recent publications have shown that synergy between PARP inhibition and either ionizing radiation or chemotherapy depends on functional TP53 [ 45 , 46 ]. Furthermore, reactivation of mutant TP53 in combination with olaparib showed highly effective tumour growth inhibition in pre-clinical models of TP53 mutant TNBC [47] .…”

Section: Discussionmentioning

confidence: 99%

Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity

et al. 2020

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Background PARP inhibitors are active in various tumour types beyond BRCA -mutant cancers, but their activity and molecular correlates in colorectal cancer (CRC) are not well studied. Methods Mutations and genome-wide mutational patterns associated with homologous recombination deficiency (HRD) were investigated in 255 primary CRCs with whole-exome sequencing and/or DNA copy number data. Efficacy of five PARP inhibitors and their molecular correlates were evaluated in 93 CRC cell lines partly annotated with mutational-, DNA copy number-, and/or gene expression profiles. Post-treatment gene expression profiling and specific protein expression analyses were performed in two pairs of PARP inhibitor sensitive and resistant cell lines. Findings A subset of microsatellite stable (MSS) CRCs had truncating mutations in homologous recombination-related genes, but these were not associated with genomic signatures of HRD. Eight CRC cell lines (9%) were sensitive to PARP inhibition, but sensitivity was not predicted by HRD-related genomic and transcriptomic signatures. In contrast, drug sensitivity in MSS cell lines was strongly associated with TP53 wild-type status (odds ratio 15.7, p = 0.023) and TP53-related expression signatures. Increased downstream TP53 activity was among the primary response mechanisms, and TP53 inhibition antagonized the effect of PARP inhibitors. Wild-type TP53-mediated suppression of RAD51 was identified as a possible mechanism of action for sensitivity to PARP inhibition. Interpretation PARP inhibitors are active in a subset of CRC cell lines and preserved TP53 function may increase the likelihood of response.

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Section: Discussionmentioning

confidence: 99%

Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity

et al. 2020

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“…PARP inhibitor treated residual cells undergo G2-M phase cell cycle arrest, but enhance γH2AX, RAD15 and DMC1 foci leading to accelerated DNA repair mechanism [ 167 ]. Other studies in colorectal cancer [ 168 ] have shown that combination of PARP inhibitors with radiotherapy and chemotherapy sensitises CSCs to the effect of given therapy. Recent clinical trials in ovarian cancer, which includes PARP inhibitors in combination with Bevacizumab or chemotherapy, have shown promising results in terms of overall all survival and progression-free survival [ 164 , 169 – 171 ].…”

Section: Ovarian Cancermentioning

confidence: 99%

The attributes of plakins in cancer and disease: perspectives on ovarian cancer progression, chemoresistance and recurrence

et al. 2021

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The plakin family of cytoskeletal proteins play an important role in cancer progression yet are under-studied in cancer, especially ovarian cancer. These large cytoskeletal proteins have primary roles in the maintenance of cytoskeletal integrity but are also associated with scaffolds of intermediate filaments and hemidesmosomal adhesion complexes mediating signalling pathways that regulate cellular growth, migration, invasion and differentiation as well as stress response. Abnormalities of plakins, and the closely related spectraplakins, result in diseases of the skin, striated muscle and nervous tissue. Their prevalence in epithelial cells suggests that plakins may play a role in epithelial ovarian cancer progression and recurrence. In this review article, we explore the roles of plakins, particularly plectin, periplakin and envoplakin in disease-states and cancers with emphasis on ovarian cancer. We discuss the potential role the plakin family of proteins play in regulating cancer cell growth, survival, migration, invasion and drug resistance. We highlight potential relationships between plakins, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) and discuss how interaction of these processes may affect ovarian cancer progression, chemoresistance and ultimately recurrence. We propose that molecular changes in the expression of plakins leads to the transition of benign ovarian tumours to carcinomas, as well as floating cellular aggregates (commonly known as spheroids) in the ascites microenvironment, which may contribute to the sustenance and progression of the disease. In this review, attempts have been made to understand the crucial changes in plakin expression in relation to progression and recurrence of ovarian cancer.

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“…CRC cells with short hairpin RNA depletion of ataxia telangiectasia mutated protein kinase are sensitive to olaparib, and the depletion of p53 enhances this sensitivity[ 101 ]. The combination of niraparip or rucaparip with the topoisomerase I inhibitor irinotecan obtained results showing enhanced anticancer efficacy targeting CRC cells regardless of microsatellite status[ 102 , 103 ]. Veliparib could be more sensitive to CRC cells undergoing mutations in mismatch repair or mutS Homolog 3 genes, and talazoparib could increase antitumor effects through the formation of DNA a double-strand break in CRC cell lines and xenograft animal models with wild-type BRCA genes[ 104 , 105 ].…”

Section: Non-clinical and Clinical Studies On Crc Treatmentmentioning

confidence: 99%

Poly adenosine diphosphate-ribosylation, a promising target for colorectal cancer treatment

Jeong¹,

Park²

2021

WJGO

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The development of colorectal cancer (CRC) can result from changes in a variety of cellular systems within the tumor microenvironment. Particularly, it is primarily associated with genomic instability that is the gradual accumulation of genetic and epigenetic changes consisting of a characteristic set of mutations crucial for pathways in CRC progression. Based on this background, the potential to focus on poly [adenosine diphosphate (ADP)-ribose] polymerase (PARP)-1 and poly-ADP ribosylation (PARylation) as the main causes of malignant formation of CRC may be considered. One of the important functions of PARP-1 and PARylation is its deoxyribonucleic acid (DNA) repair function, which plays a pivotal role in the DNA damage response and prevention of DNA damage maintaining the redox homeostasis involved in the regulation of oxidation and superoxide. PARP-1 and PARylation can also alter epigenetic markers and chromatin structure involved in transcriptional regulation for the oncogenes or tumor suppressor genes by remodeling histone and chromatin enzymes. Given the high importance of these processes in CRC, it can be considered that PARP-1 and PARylation are at the forefront of the pathological changes required for CRC progression. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 and PARylation in CRC related to the aforementioned roles; furthermore, it presents a summary of recent approaches with PARP-1 inhibition in non-clinical and clinical studies targeting CRC. This understanding could help embrace the importance of targeting PARP-1 and PARylation in the treatment of CRC, which may present the potential to identify various research topics that can be challenged both non-clinically and clinically.

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Sensitization of colorectal cancer to irinotecan therapy by PARP inhibitor rucaparib

Cited by 34 publications

References 55 publications

Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity

Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity

The attributes of plakins in cancer and disease: perspectives on ovarian cancer progression, chemoresistance and recurrence

Poly adenosine diphosphate-ribosylation, a promising target for colorectal cancer treatment

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