Abstract LB-265: The novel oral Chk1 inhibitor, SRA737, is active in both PARP inhibitor resistant and <i>CCNE1</i> amplified high grade serous ovarian cancers
Bibliographic record
Abstract
Abstract High grade serous ovarian cancers (HGSOC) have defective homologous recombination (HR) genes in 50% of cases, while a distinct 20% demonstrate CCNE1 amplification (CCNE1amp). HR-deficient HGSOC are initially sensitive to Poly(ADP-ribose) polymerase inhibitors (PARPi) but drug resistance ultimately emerges. CCNE1amp HGSOC show resistance to PARPi and platinum treatments. Here, we investigated the anti-tumor activity of the potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), SRA737, in both acquired PARPi-resistant and CCNE1amp HGSOC models. HR-deficiencies and CCNE1amp are known to increase replication stress, leading to increased reliance on Chk1, a key regulator of cell cycle progression and the replication stress response. We hypothesized that Chk1 inhibition by SRA737 will result in increased replication stress, inducing subsequent cell death and tumor regression in both PARPi-resistant and CCNE1amp ovarian cancer models. In colony formation assays, SRA737 monotherapy decreased cell survival in HR-deficient, PARPi-resistant and CCNE1amp cells. Additionally, the combination of SRA737 with PARPi was synergistic in decreasing colony formation in HR-deficient (PEO1, best coefficient of drug interaction (CDI)=0.53; JHOS4, CDI=0.45) and PARPi-resistant cell models (PEO1-PR, CDI=0.11; PEO4, CDI=0.08). SRA737 treatment led to a dose-dependent increase in the replication stress marker pCHK1 (S345), confirming an on-target drug effect in PARPi-resistant (PEO1-PR) and CCNE1amp (OVCAR3) cells. Furthermore, treatment with SRA737 induced gH2AX (indicator of DNA damage) which increased modestly in combination with PARPi. SRA737 was also evaluated in a PARPi-resistant PDX model as well as in CCNE1amp in vivo mouse models. Preliminary evidence in a PARPi resistant PDX model demonstrated tumor growth inhibitory activity of SRA737 in combination with PARPi. Consistent with in vitro activity, SRA737 inhibited tumor growth in an OVCAR3 xenograft model. Lastly, in an orthotopic PDX model established from a platinum-resistant CCNE1amp ovarian cancer patient, SRA737 monotherapy caused significant tumor regression, similar to SRA737 in combination with PARPi. Strategies to optimize treatments for PARPi-resistant HGSOC, as well as for platinum-resistant CCNE1amp HGSOC, are needed. In PARPi-resistant models, SRA737 is active as a monotherapy, and the combination of SRA737 with PARPi demonstrated synergy. In CCNE1amp tumors, SRA737 showed profound activity as a monotherapy in this PARPi-resistant model. SRA737 is a new potent and selective Chk1 inhibitor that demonstrated activity in acquired PARPi-resistant as well as CCNE1amp preclinical cancer models, warranting further development in these HGSOC subgroups. Citation Format: Haineng Xu, Sergey Medvedev, Ashka Pandya, Hyoung Kim, Yasuto Kinose, Eric Brown, Ryan J. Hansen, Bryan Strouse, Snezana Milutinovic, Christian Hassig, Fiona Simpkins. The novel oral Chk1 inhibitor, SRA737, is active in both PARP inhibitor resistant and CCNE1 amplified high grade serous ovarian cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-265.
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) | 0.002 | 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".