Abstract A079 Mechanisms of chemotherapy resistance in rhabdomyosarcoma
Bibliographic record
Abstract
Abstract Background: Rhabdomyosarcoma (RMS) is a childhood cancer that originates from soft tissue and shares features with skeletal muscle. RMS patients are treated with a combination of radiation, surgical resection, and chemotherapy (VAC; vincristine, actinomycin D and cyclophosphamide). Unfortunately, 30% of patients eventually develop relapsed tumors due to resistance to VAC or radiation, of whom have an abysmal 17% five-year survival rate. To date, the mechanisms underlying resistance to VAC is poorly understood in RMS tumors, which are desperately needed for devising new therapeutic avenues to target VAC chemoresistance and improve the outcomes for these patients. Methods: We have recently generated long-term VAC-resistant RMS cell lines (from RD and Rh41 parental lines) to model chemoresistance. These cell lines were acclimated to high dose VAC over a 3-month period. Afterwards, single clones were isolated from these chemoresistant cell lines and assessed for upregulation of the PIK3CA/AKT/ABC transporter pathway by Western blot analysis. Results: We find that within the pool of resistant clones, there are two distinct pathways that are upregulated to promote VAC-resistance, one that elevates the PIK3CA/AKT/ABC transport pathway to rapidly efflux drugs from RMS cells. Astonishingly, this same drug resistance pathway is activated in both fusion-positive and fusion-negative RMS. The upregulated ABC transporters are well known drug efflux pumps and include ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP. We next show that the increased transcription of these ABC transporters occurs through an AKT-dependent mechanism – akin to that described by our group for an investigational chemotherapy that combines DNA damaging agent temozolomide with Olaparib PARP-inhibitor (OT). Using an inhibitor of PIK3CA signaling, Alpelisib, we show that we can resensitize these chemoresistant cell lines to VAC and OT. Conclusions: VAC-resistance occurs in part through PIK3CA/AKT signaling to promote drug efflux. The PIK3CA/AKT pathway can be therapeutically targeted to resensitize tumors to VAC. Future studies will focus on determining the mechanisms of drug resistance in tumors that fail to upregulate the PIK3CA/AKT/ABC transport pathway. Citation Format: Sabateeshan Mathavarajah, Yueyang Wang, Yun Wei, Diego Antelo, David M. Langenau. Mechanisms of chemotherapy resistance in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A079.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".