2025 Hyper Recent •CC0 1.0 Universal

This work is dedicated to the public domain. No rights reserved.

Access Preprint From Server
January 20th, 2025
Version: 1
Brown University
cancer biology
biorxiv

DNA polymerase beta expression in head & neck cancer modulates the poly(ADP-ribose)-mediated replication checkpoint

Khan, M. M.Open in Google Scholar•Roos, W. P.Open in Google Scholar•Angajala, A.Open in Google Scholar•Gibbs, D. Y.Open in Google Scholar•Liu, J. C.Open in Google Scholar•Ragin, C.Open in Google Scholar•Sobol, R. W.Open in Google Scholar

Head and Neck Squamous Cell Carcinoma (HNSCC) imposes a significant health burden, necessitating innovative therapeutic strategies to enhance treatment efficacy. Current treatments such as surgery, radiation, and chemotherapy have limited effectiveness and yield severe side effects, emphasizing the need for targeted therapies. We have focused on DNA polymerase beta (Pol{beta}) and its roles in replication stress, cellular responses to DNA damaging therapies, and DNA damage response modifiers. Our investigations reveal a regulatory role for base excision repair (BER) proteins, including Pol{beta}, in the cellular response to inhibitors of poly(ADP-ribose) glycohydrolase (PARG), an enzyme involved in poly(ADP-ribose) (PAR) degradation. The inhibition of PARG, in HNSCC cells, elicits replication stress. Further, this activates the PAR-induced S-phase/ATR checkpoint, leading to a block to replication, cell cycle arrest, and the onset of apoptosis. However, Pol{beta} overexpression mitigates this response, reducing replication-stress induced PAR foci formation, suggesting a modulation of replication checkpoint activation. We found that PARG inhibitor treatment is ineffective on HNSCC cells that overexpress Pol{beta}, implying that the PARG inhibitor-induced PAR and apoptotic response is dependent on the level of Pol{beta}. Further, our in vitro experiments demonstrate that combining PARG and ATR/CHK1 inhibitors overcomes Pol{beta}-mediated treatment resistance in HNSCC cells, producing enhanced effects as compared to the individual treatment conditions. Our findings suggest a possible treatment paradigm for HNSCC, employing ATR or CHK1 inhibitors in combination with PARG inhibitors. This strategy offers a promising path for more effective HNSCC treatments, potentially overcoming Pol{beta}-related resistance.

Similar Papers

biorxiv
Fri Apr 25 2025
TIGIT expression dictates the immunosuppressive reprogramming of myeloid cells in glioblastoma
Glioblastoma (GBM) is a deadly brain cancer with near-universal recurrence despite maximal treatment for which new innovations are sorely needed. Immunotherapy has yet to make significant gains in GBM treatment despite revolutionizing other cancer therapies, due in part to GBM-mediated immune suppression. This immune derangement proceeds through several mechanisms, but increasing evidence points t...
Asad, M.
•
Inocencio, J.
•
Mitrasinovic, S.
•
Aoki, M.
...•
Himes, B. T.
biorxiv
Fri Apr 25 2025
The inherent fragility of collective proliferative control
Tissues achieve and maintain their sizes through active feedback, whereby cells collectively regulate proliferation and differentiation so as to facilitate homeostasis and the ability to respond to disturbances. One of the best understood feedback mechanisms--renewal control--achieves remarkable feats of robustness in determining and maintaining desired sizes. Yet in a variety of biologically rele...
Caldwell, M. G.
•
Lander, A. D.
biorxiv
Fri Apr 25 2025
Deep visual multi-omics profiling reveals mechanisms that underlie cancer cell differentiation and aggressiveness in clear cell renal cell carcinoma
Clear cell renal cell carcinoma (ccRCC) exhibits significant intra-tumoral heterogeneity (ITH) at both morphological and genetic levels, complicating treatment and contributing to disease progression. Among these, rhabdoid ccRCCs stand out as highly aggressive tumors distinguished by cells with unique morphological features and poor clinical outcomes. However, the correlation between distinct morp...
Bolck, H. A.
•
Migh, E.
•
Kriston, A.
•
Zajac, N.
...•
Moch, H.
biorxiv
Fri Apr 25 2025
Repurposing Quetiapine as an Adjuvant Therapeutic Agent for Triple-Negative Breast Cancer
Background: The lack of a molecular target in triple-negative breast cancer (TNBC) makes it one of the most challenging breast cancers to treat. Current standard-of-care primarily relies on cytotoxic chemotherapy and radiotherapy, but long-term outcomes remain poor largely due to early relapse, therapy resistance, and high incidents of metastases. More recently, dopamine signaling has emerged as a...
He, L.
•
Joshi, P.
•
Ioannidis, A.
•
Kathiravan, A.
...•
Pajonk, F.
biorxiv
Fri Apr 25 2025
PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer
The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery. PTEN is a crucial negative regulator of the PI3K/Akt signaling pathway. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight that an elevated level of PTEN neddylation is markedly associated with resistance to palbociclib...
Liu, F.
•
Liu, W.
•
Tan, Y.
•
Shang, Y.
...•
Xie, P.
biorxiv
Thu Apr 24 2025
A whole genomic CRISPR-Cas9 screen identifies the amino acid transporter SLC43A1 (LAT3) as a major determinant of oxaliplatin sensitivity in colorectal cancer cells
Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States, with a five-year survival rate of 65%. Oxaliplatin was the first platinum drug shown to improve CRC patient outcomes and is now a common adjuvant therapy for advanced disease, yet 90% of patients develop resistance. Oxaliplatin was developed as a third-generation derivative of cisplatin, but recent evidence ...
Pawar, N. R.
•
Wade, H. M.
•
Jackson, Z.
•
Poungpeth, N.
...•
Gottesman, M. M.
biorxiv
Thu Apr 24 2025
BRCA2 reversion mutation-independent resistance to PARP inhibition in prostate cancer through loss of function perturbations in the DNA pre-replication complex
Recent approvals of PARP inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer (mCRPC) necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50-80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into wh...
Pappas, K. J.
•
Ferrari, M.
•
Smith, P.
•
Nandakumar, S.
...•
Sawyers, C.
biorxiv
Thu Apr 24 2025
TGFb Regulated Small GTPase RHOV interact with PEAK1 and drive MYC Expression to Promote Cellular Proliferation, Migration and Etoposide resistance
Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, driven by tumor heterogeneity, metastasis, and therapeutic resistance. While Rho GTPases are well-established regulators of oncogenic processes, the role of the atypical GTPases in NSCLC remains unexplored. Here, we identified RHOV as one of the commonly upregulated Rho GTPases in NSCLC. Analysis of four indepe...
Chatterjee, A.
•
Acharya, D.
•
Bhandari, N.
•
Bhat, P.
...•
Shukla, S.
biorxiv
Thu Apr 24 2025
Chromosomal Aneuploidy in Normal, Non-Neuronal Brain Nuclei of Glioblastoma Patients is Not a Cancer Driver
Aneuploidy is a hallmark of cancers, including high-grade glioma (GBM), one of the most aggressive brain tumors. To assess whether increased aneuploidy already occurs in normal brain tissue of GBM patients, we performed single-nucleus whole-genome sequencing on 225 non-neuronal cortical nuclei from 12 disease-free individuals and 6 GBM patients, in the latter analyzing both tumor and non-tumor dis...
Montagna, C.
•
Albert, O.
•
Sun, S.
•
Lin, J.-R.
...•
Vijg, J. V.
biorxiv
Thu Apr 24 2025
Neoantigens drive adoptively transferred CD8 T cells to long-lived effectors mediated by lymph node trafficking
Adoptive transfer of neoantigen-reactive T lymphocytes mediates potent responses against solid tumors in patients while often limiting toxicity to normal tissues; however, the mechanisms governing the trafficking, activation, and superior antitumor function of infused T cells remain unknown. Using a clinically relevant TCR-transgenic T cell therapy model, we examined CD8 T cell responses to melano...
Wittling, M. C.
•
Rivera Reyes, A. M.
•
Wyatt, M. M.
•
Smith, A. S.
...•
Knochelmann, H. M.