ATR and PKMYT1 Inhibition Resensitizes a Subset of TNBC Patient-Derived Models to Carboplatin, Inducing Mitotic Catastrophe
Bibliographic record
Abstract
Triple-negative breast cancer (TNBC) is associated with poor prognosis and is mainly treated with chemotherapy-based regimens, often including carboplatin. Resistance to carboplatin is a common clinical issue that is either initially present or develops with treatment. Overcoming this resistance is a significant clinical challenge, which highlights the need for novel therapeutic strategies. We used a pooled short hairpin RNA screening approach with a chemoresistant TNBC patient-derived xenograft (PDX) cell line (PDXC) to identify targets in which knockdown would enhance the efficacy of carboplatin. This screening led to the identification of the ataxia telangiectasia and Rad3-related (ATR) gene as a key therapeutic vulnerability. Inhibiting ATR with BAY1895344 or AZD6738 resensitized carboplatin-resistant PDXCs and PDXs to carboplatin, resulting in an increase in DNA damage and apoptosis. ATR inhibition prevents carboplatin-resistant cells from effectively engaging the S and G2-M checkpoints required for DNA repair, leading to mitotic catastrophe. We further identified that the addition of ATR inhibitors to carboplatin enabled the FOXM1-targeted gene program, leading to premature passage into mitosis. Moreover, targeting PKMYT1, a regulator of cyclin-dependent kinase 1 controlling the G2-M checkpoint, through knockdown or with the novel PKMYT1 inhibitor RP-6306, also enhanced carboplatin efficacy in our TNBC PDXC. Molecular factors associated with the response to the ATR inhibitor/carboplatin combination included low RNA levels of PKMYT1. These results underscore the pivotal roles of ATR and PKMYT1 in mediating resistance to carboplatin in TNBC and support targeting these pathways to overcome carboplatin resistance in this disease. SIGNIFICANCE: Patients with TNBC are mostly treated with chemotherapy, including carboplatin. Given that patients often develop resistance to carboplatin, finding a way to resensitize them to this agent is paramount. Our work highlights the use of ATR and PKMYT1 inhibitors to resensitize chemoresistant patient-derived models to carboplatin. These studies in patient-derived models establish the basis for novel therapeutic drug combinations to overcome carboplatin resistance in patients with TNBC.
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) | 0.001 | 0.000 |
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".