Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2
Bibliographic record
Abstract
// Mateusz Rytelewski 1, 6 , Saman Maleki Vareki 6 , Lingegowda S. Mangala 3, 5 , Larissa Romanow 1 , Dahai Jiang 3, 4 , Sunila Pradeep 4 , Christian Rodriguez-Aguayo 3, 4 , Gabriel Lopez-Berestein 4, 5 , Rene Figueredo 2 , Peter J. Ferguson 6 , Mark Vincent 2, 6 , Anil K. Sood 3, 5, 7 , James D. Koropatnick 1, 2, 6 1 Department of Microbiology and Immunology, Western University, London, ON, Canada 2 Department of Oncology, Western University, London, ON, Canada 3 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Lawson Health Research Institute, London, ON, Canada 7 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: James D. Koropatnick, e-mail: jkoropat@uwo.ca Keywords: DNA repair, resistance, BRCA2, PARP1, antisense Received: February 09, 2016     Accepted: February 17, 2016     Published: March 03, 2016 ABSTRACT Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".