Epigenetic reprogramming and potential application of epigenetic-modifying drugs in acquired chemotherapeutic resistance

Ponnusamy, Logeswari; Mahalingaiah, Prathap Kumar S.; Singh, Kamaleshwar P.

doi:10.1016/bs.acc.2019.07.011

Cited by 28 publications

(28 citation statements)

References 116 publications

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“…The concept of re‐sensitization therapy with HMAs is currently being evaluated for solid tumors 17,18 . There are several reasons to suggest that re‐sensitization therapy may be particularly effective for testicular germ cell tumors (TGCTs).…”

Section: Discussionmentioning

confidence: 99%

“…The concept of re-sensitization therapy with HMAs is currently being evaluated for solid tumors. 17,18 There are several reasons to suggest that re-sensitization therapy may be particularly effective for testicular germ cell tumors (TGCTs). TGCTs appear to have distinct epigenetic profiles, including hypomethylated DNA that has been suggested to correlate with sensitivity to cisplatin.…”

Section: Discussionmentioning

confidence: 99%

“…For some solid tumor types, there is a correlation between increased DNA methylation and resistance to chemotherapy that can be reversed by hypomethylating agents (HMAs) 17,18 . Resensitization is often accompanied by re‐expression of tumor suppressor genes.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16] For some solid tumor types, there is a correlation between increased DNA methylation and resistance to chemotherapy that can be reversed by hypomethylating agents (HMAs). 17,18 Resensitization is often accompanied by re-expression of tumor suppressor genes. A number of preclinical and phase I and phase II clinical studies in ovarian cancer indicate the potential of HMAs as re-sensitizers in platinum-resistant disease.…”

Section: Introductionmentioning

confidence: 99%

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A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer

et al. 2020

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Purpose Germ cell tumors (GCTs) are cured with therapy based on cisplatin, although a clinically significant number of patients are refractory and die of progressive disease. Based on preclinical studies indicating that refractory testicular GCTs are hypersensitive to hypomethylating agents (HMAs), we conducted a phase I trial combining the next‐generation HMA guadecitabine (SGI‐110) with cisplatin in recurrent, cisplatin‐resistant GCT patients. Methods Patients with metastatic GCTs were treated for five consecutive days with guadecitabine followed by cisplatin on day 8, for a 28‐day cycle for up to six cycles. The primary endpoint was safety and toxicity including dose‐limiting toxicity (DLT) and maximum tolerated dose (MTD). Results The number of patients enrolled was 14. The majority of patients were heavily pretreated. MTD was determined to be 30 mg/m2 guadecitabine followed by 100 mg/m2 cisplatin. The major DLTs were neutropenia and thrombocytopenia. Three patients had partial responses by RECIST criteria, two of these patients, including one with primary mediastinal disease, completed the study and qualified as complete responses by serum tumor marker criteria with sustained remissions of 5 and 13 months and survival of 16 and 26 months, respectively. The overall response rate was 23%. Three patients also had stable disease indicating a clinical benefit rate of 46%. Conclusions The combination of guadecitabine and cisplatin was tolerable and demonstrated activity in patients with platinum refractory germ cell cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer

et al. 2020

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“…Like most complex genomic phenomena, acquired resistance to targeted therapies has diverse underlying drivers including both pathway-dependent mechanisms such as bypass activation, secondary mutation or downstream activation, and pathway-independent mechanisms such as tumor microenvironment, epithelial-mesenchymal transition (EMT) or epigenetic modulation [ 24 ]. Despite its role in tumorigenesis, the epigenetic modifications have been noticed to associate with acquired drug resistance in recent years [ 25 ]. And our analyses of genomic alterations pre- and post-pazopanib resistance suggested that epigenetic regulation might play a role in acquired TKI-resistance.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome sequencing reveals potential mechanisms of drug resistance to FGFR3-TACC3 targeted therapy and subsequent drug selection: towards a personalized medicine

et al. 2020

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Background Drug resistance is a major obstacle to effective cancer therapy. In order to detect the change in tumor genomic states under drug selection pressure, we use next-generation sequencing technology to investigate the underlying potential mechanisms of drug resistance. Methods In our study, we presented a bladder cancer patient who had been a bona fide responder to first-line gemcitabine plus cisplatin regimen and second-line pazopanib (tyrosine kinase inhibitor (TKI) for FGFR3-TACC3 fusion) but finally had disease progression as an ideal case for showing genomic alteration during drug resistance. We applied whole-exome sequencing and ultra-deep target sequencing to the patient pre- and post- pazopanib resistance. Protein-protein interaction (PPI) network and Gene Ontology (GO) analyses were used to analysis protein interactions and genomic alterations. Patient-derived xenograft (PDX) model was built to test drug sensitivity. Results Twelve mutations scattered in 12 genes were identified by WES pre- pazopanib resistance, while 63 mutations in 50 genes arose post- pazopanib resistance. PPI network showed proteins from multiple epigenetic regulator families were involved post- pazopanib resistance, including subunits of chromatin remodeler SWI/SNF complex ARID1A/1B and SMARCA4, histone acetylation writers CREBBP, histone methylation writer NSD1 and erasers KDM6A/5A. GO enrichment analysis showed pazopanib resistance genes were prominently tagged for chromatin modification, transcription, as well as gland development, leaving genes with the best adaptive FGFR TKI-coping mechanisms. In addition, significantly elevated tumor mutational burden suggested possible utility of immunotherapy. Intriguingly, PDX model suggested that, sensitivity to original chemotherapy regimen (cisplatin) was restored in patient tumor post-pazopanib. Conclusions Epigenetic regulation may play a role in acquired TKI resistance. Our study traced the complete tumor genomic variation course from chemo-resistant but TKI-sensitive to TKI-resistant but chemo-(re) sensitive, revealing the potential complex dynamic drug-driven mechanisms of resistance.

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YTHDF2 promotes intrahepatic cholangiocarcinoma progression and desensitises cisplatin treatment by increasing CDKN1B mRNA degradation

Huang

Zhu

et al. 2022

Clinical & Translational Med

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Background Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer with exceedingly poor prognosis, and chemoresistance is a huge challenge for treatment. N6‐methyladenosine (m 6 A) modification plays an important role in the progression and chemoresistance of cancers. We aimed to investigate the oncogenic function and therapeutic significance of the m 6 A binding protein, YTH domain family 2 (YTHDF2), in ICC progression and cisplatin‐based chemotherapy. Methods Several independent data sets were used to assess the expression of YTHDF2 in ICC, particularly in chemoresistant ICC. Knockdown and overexpression were used to evaluate the effects of YTHDF2 on tumourigenesis and cisplatin response in ICC. Multi‐omics sequencing was performed to identify target genes. RIP, dual luciferase reporter, RNA stability experiment and loss‐of‐function assays were conducted to study the mechanisms underlying the oncogenic function of YTHDF2. Furthermore, patient‐derived xenograft (PDX) model was established to determine the effect of combination treatment of YTHDF2 siRNA and cisplatin in ICC. Results Our study showed that YTHDF2 was upregulated in ICC tissues, particularly in chemoresistant ICC tissues, and correlated with poor prognosis. Furthermore, silencing YTHDF2 led to inhibited proliferation, promoted apoptosis and G0/G1 cell cycle arrest. Its downregulation also enhanced DNA damage and sensitised ICC cells to cisplatin. YTHDF2 overexpression exerted the opposite results. Integration analysis using RNA‐seq, MeRIP‐seq and anti‐YTHDF2 RIP‐seq elucidated the role of YTHDF2 in tumourigenesis and cisplatin‐desensitising function by promoting the degradation of cyclin‐dependent kinase inhibitor 1B (CDKN1B) mRNA in an m 6 A‐dependent manner. Downregulation of CDKN1B increased the YTHDF2 silencing‐induced influence on tumourigenesis and cisplatin response to ICC. In addition, the combination treatment of YTHDF2 siRNA and cisplatin significantly enhanced the anti‐tumour effect of cisplatin in a chemoresistant ICC PDX model. Conclusions YTHDF2 exhibits tumour oncogenic and cisplatin‐desensitising properties, which may offer insight into the development of novel combination therapeutic strategies for ICC.

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Epigenetic reprogramming and potential application of epigenetic-modifying drugs in acquired chemotherapeutic resistance

Cited by 28 publications

References 116 publications

A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer

A phase 1 study of combined guadecitabine and cisplatin in platinum refractory germ cell cancer

Whole-exome sequencing reveals potential mechanisms of drug resistance to FGFR3-TACC3 targeted therapy and subsequent drug selection: towards a personalized medicine

YTHDF2 promotes intrahepatic cholangiocarcinoma progression and desensitises cisplatin treatment by increasing CDKN1B mRNA degradation

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