Translesion DNA synthesis mediates acquired resistance to olaparib plus temozolomide in small cell lung cancer

Stanzione, Marcello; Zhong, Jun; Wong, Edmond; LaSalle, Thomas J.; Wise, Jillian F; Simoneau, Antoine; Myers, David T.; Phat, Sarah; Sade-Feldman, Moshe; Lawrence, Michael S.; Hadden, M. Kyle; Zou, Lee; Farago, Anna F.; Dyson, Nicholas J.; Drapkin, Benjamin J.

doi:10.1126/sciadv.abn1229

Cited by 17 publications

(7 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, the levels of CDKN1A/p21 after DNA damage do not always increase as discussed previously regarding Translesion DNA Synthesis (TLS) [78,79]. TLS is a well-conserved process by which the cell can bypass DNA damage and continue the cell cycle, mediated by specialised polymerases; this process can result in tumour resistance to DNA-damaging reagents during cancer treatment [174][175][176].…”

Section: Discussion and Future Directionsmentioning

confidence: 90%

CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?

Manousakis,

Miralles,

Esquerda

et al. 2023

IJMS

View full text Add to dashboard Cite

Cyclin-dependent kinase inhibitor 1A (Cip1/Waf1/CDKN1A/p21) is a well-established protein, primarily recognised for its pivotal role in the cell cycle, where it induces cell cycle arrest by inhibiting the activity of cyclin-dependent kinases (CDKs). Over the years, extensive research has shed light on various additional mechanisms involving CDKN1A/p21, implicating it in processes such as apoptosis, DNA damage response (DDR), and the regulation of stem cell fate. Interestingly, p21 can function either as an oncogene or as a tumour suppressor in these contexts. Complicating matters further, the expression of CDKN1A/p21 is elevated in certain tumour types while downregulated in others. In this comprehensive review, we provide an overview of the multifaceted functions of CDKN1A/p21, present clinical data pertaining to cancer patients, and delve into potential strategies for targeting CDKN1A/p21 as a therapeutic approach to cancer. Manipulating CDKN1A/p21 shows great promise for therapy given its involvement in multiple cancer hallmarks, such as sustained cell proliferation, the renewal of cancer stem cells (CSCs), epithelial–mesenchymal transition (EMT), cell migration, and resistance to chemotherapy. Given the dual role of CDKN1A/p21 in these processes, a more in-depth understanding of its specific mechanisms of action and its regulatory network is imperative to establishing successful therapeutic interventions.

show abstract

Section: Discussion and Future Directionsmentioning

confidence: 90%

CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?

Manousakis,

Miralles,

Esquerda

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

“…2G and ref. 47 ). Nearly all new mutations were C>T transitions characteristic of TMZ (SBS11 in COSMIC), which became so abundant that they supplanted the tobacco-induced C>A transversion signature (SBS4 in COSMIC; Fig.…”

Section: Resultsmentioning

confidence: 99%

Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs

Pal Choudhuri,

Girard,

Lim

et al. 2024

Cancer Discovery

Self Cite

View full text Add to dashboard Cite

Small cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here, we present a pre-clinical system that recapitulates acquired cross-resistance, developed from 51 patient-derived xenograft (PDX) models. Each model was tested in vivo against three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These drug-response profiles captured hallmark clinical features of SCLC, such as the emergence of treatment-refractory disease after early relapse. For one patient, serial PDX models revealed that cross-resistance was acquired through MYC amplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that MYC paralog amplifications on ecDNAs were recurrent in relapsed cross-resistant SCLC, and this was corroborated in tumor biopsies from relapsed patients. We conclude that ecDNAs with MYC paralogs are recurrent drivers of cross-resistance in SCLC.

show abstract

“…Studies have shown that Rad18-induced ubiquitination of PCNA as well as error-prone polymerases play multiple roles in tumorigenesis [182,183]. As biological processes that contribute to oncogenesis are often also involved in the cellular response to anti-cancer drugs, it is unsurprising that a number of studies [184,185] have also shown that altered expression of genes associated with low-fidelity DNA polymerases can also impact cellular sensitivity to cancer chemotherapeutic agents known to produce DPCs. The role of error-prone DNA polymerases is further explored in a number of recent review articles [186][187][188].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Enzymatic Processing of DNA–Protein Crosslinks

Essawy,

Campbell

2024

Genes

View full text Add to dashboard Cite

DNA–protein crosslinks (DPCs) represent a unique and complex form of DNA damage formed by covalent attachment of proteins to DNA. DPCs are formed through a variety of mechanisms and can significantly impede essential cellular processes such as transcription and replication. For this reason, anti-cancer drugs that form DPCs have proven effective in cancer therapy. While cells rely on numerous different processes to remove DPCs, the molecular mechanisms responsible for orchestrating these processes remain obscure. Having this insight could potentially be harnessed therapeutically to improve clinical outcomes in the battle against cancer. In this review, we describe the ways cells enzymatically process DPCs. These processing events include direct reversal of the DPC via hydrolysis, nuclease digestion of the DNA backbone to delete the DPC and surrounding DNA, proteolytic processing of the crosslinked protein, as well as covalent modification of the DNA-crosslinked proteins with ubiquitin, SUMO, and Poly(ADP) Ribose (PAR).

show abstract

Translesion DNA synthesis mediates acquired resistance to olaparib plus temozolomide in small cell lung cancer

Cited by 17 publications

References 82 publications

CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?

CDKN1A/p21 in Breast Cancer: Part of the Problem, or Part of the Solution?

Acquired Cross-Resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification of MYC Paralogs

Enzymatic Processing of DNA–Protein Crosslinks

Contact Info

Product

Resources

About