Abstract A069 The role of <i>ABCB1</i> in doxorubicin resistant SMARCB1-deficient cancers
Bibliographic record
Abstract
Abstract SMARCB1 is a tumor suppressor gene and encodes a core subunit of the SWI-SNF chromatin remodeling complex. Loss of SMARCB1 leads to the development of highly aggressive pediatric malignancies, termed “SMARCB1-deficient cancers.” This includes malignant rhabdoid tumor, atypical teratoid rhabdoid tumor (ATRT), and renal medullary carcinoma (RMC). Survival rates in these patients remain low, and resistance to chemotherapeutic agents used to treat these cancers are common. One such chemotherapy is doxorubicin. Therefore, this project aims to reveal and understand the mechanisms of doxorubicin resistance in SMARCB1-deficient cancers. To address this question, we generated doxorubicin resistant (DR) cells from one ATRT and two RMC primary cell lines (BT16, PEDS005T, and RCRF1009T respectively) utilizing a dose escalation approach. This resulted in DR cell lines that are 10-fold to 30-fold resistant compared to the parental cell line. Upon generation of these stably resistant cell lines, we profiled their transcriptomes by RNA-sequencing and found an upregulation of the multidrug transporter ABCB1, also known as MDR1. To further probe these cell lines, we performed whole-genome sequencing (WGS) on two of our DR cell lines (BT16 and PEDS005T DR). Here, we found a chromosome 7 aneuploidy in BT16 DR cells, but no aneuploidy or mutations were seen in PEDS005T DR cells. ABCB1 is located on chromosome 7. We confirmed this aneuploidy via karyotyping. The mechanism of ABCB1 upregulation in the RMC DR cell lines remains unknown, suggesting multiple modalities leading to ABCB1 upregulation. We then overexpressed ABCB1 in two ATRT parental cell lines (BT16 and CHLA-06-ATRT) and one RMC cell line (PEDS005T) which led to enhanced short-term resistance. This contrasted to JMSU, a SMARCB1 wild-type bladder cancer cell line, where there was stable resistance. Together, this suggests that ABCB1 may be necessary but not sufficient to confer doxorubicin resistance in these SMARCB1-deficient cancer cells. These preliminary findings suggest that despite a common genetic driver (loss of SMARCB1), there may be different pathways to developing resistance to the DNA-damaging agent, doxorubicin. Furthermore, despite the well documented role of ABCB1 in drug resistance, there may be other factors involved in conferring stable resistance in the setting of SMARCB1-deficient cancers. Citation Format: Katie T. Skinner, Benjamin P. Lee, Jessica S Yoon, Andrew L. Hong. The role of ABCB1 in doxorubicin resistant SMARCB1-deficient cancers [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 A069.
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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 | 0.001 | 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".