Abstract P011: STN1 (OBFC1) promotes DNA double-strand break repair in a potentially CTC1-STN1-TEN1 (CST) complex-independent role in pancreatic cancer
Bibliographic record
Abstract
Abstract Purpose: Pancreatic cancer (PC) is an aggressive lethal tumor with an unmet need for novel therapeutic approaches. KRAS activating mutations occur in 90-95% of PC and contribute to tumor progression and resistance to therapy, including radiation. The mechanisms by which oncogenic KRAS promotes radiation resistance are critical to understand in order to identify novel therapies. Methods: We first analyzed the expression levels of DNA damage response and repair genes using Affymetrix RNA expression microarray in isogenic HCT116 and SW48 cells with KRAS wide-type and KRASG13D activating mutations to identify novel targets by which KRAS mutations may confer radiation resistance. We analyzed the expression of STN1 in pancreas normal and cancer tissues and assessed the correlation with PC clinical outcomes using TCGA dataset. Human tumor xenografts were generated to explore the role of STN1 on tumor growth in vivo. Radiation response was assessed through clonogenicity and gH2AX foci assays. Homologous recombination (HR) and non-homologous end joining (NHEJ) repair reporter assays, chromatin spreading assay, cell cycle analysis, mitotic catastrophe, Annexin-V assays were performed to investigate the mechanisms of radiation-induced cell death. Mass spectrometry analysis was performed to identify STN1 interacting proteins important in DNA damage response and further validated by immunoprecipitation and immunoblotting. Results: We find that KRAS activation increases STN1 expression to enhance DNA double strand break repair capacity in PC. STN1 is a component of the CST complex normally important for telomere duplication and maintenance. We find that STN1 is significantly upregulated in PC, especially in aggressive subtypes of PC, associates with KRAS oncogenic mutations, and correlates with poor patient clinical outcomes. Genetic silencing or pharmacologic inhibition of KRAS signaling decreases STN1 expression in PC cells, suggesting KRAS signaling positively regulates STN1 expression. Interestingly, STN1 depletion reduces tumor growth in a heterotopic model of KRAS mutant PC. Mechanistically, depletion of STN1 potentiates DNA damage, replication stress, and sensitizes PC cells to ionizing radiation independent of CTC1 and TEN1. In support of this finding, STN1 silencing reduces both HR and NHEJ repair of DSBs. Furthermore, knockdown of STN1 impairs cell cycle arrest at the G2/M phase in response to ionizing radiation, which is accompanied with increased mitotic catastrophe, radiation-induced apoptosis. Proteomic analysis reveals that STN1 physically interacts with many proteins important for DNA repair, replication and cell cycle progression, including ATM, DICER1, CEP164, and CEP250. Conclusion: Our findings have revealed a novel, potentially CST complex-independent role of STN1 in DSB repair after radiation. STN1 may function at one of the apical nodes in the DNA damage response pathway by interacting with ATM. Our findings suggest STN1 may be a promising target for improving genotoxic therapies in KRAS mutant cancers, including PC. Citation Format: Tiantian Cui, Changxian Shen, Linlin Yang, Ling Gui, Sergio Corrales-Guerrero, Sindhu Nair, Joanna M. Karasinska, James T. Topham, Xiaoli Ping, Jeremy M. Stark, Terence M. Williams.STN1 (OBFC1) promotes DNA double-strand break repair in a potentially CTC1-STN1-TEN1 (CST) complex-independent role in pancreatic cancer.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P011
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".