Biology subjects

Burnstein, K. L.

Publications and source records attributed to Burnstein, K. L..

3 recordsLinked to original sources

bioRxiv2025

BUB1B MITOTIC KINASE DRIVES THERAPY RESISTANT PROSTATE CANCER

Castration-resistant prostate cancer (CRPC) that progresses despite treatment with potent AR antagonists such as enzalutamide is a major clinical problem. Through an unbiased systems biology approach, we previously identified a therapeutically relevant seven gene set that drives CRPC. The mitotic checkpoint kinase, BUB1B (BUBR1) is a key member of this gene set, and we report here that BUB1B is a tractable and promising new therapeutic target in aggressive, treatment-resistant PC. We found that high BUB1B expression is correlated with PC progression and aggressiveness. In established CRPC cells, BUB1B depletion blocked cell proliferation through cell cycle arrest and mitosis delay. Ectopic expression of BUB1B, at levels found in CRPC, conferred castration-resistant growth of androgen-dependent PC cells in vitro and in vivo. We showed that BUB1B kinase activity was essential for CRPC progression, as only wild type (wt) BUB1B and neither of two kinase-dead mutants promoted castration-resistant growth of androgen-dependent PC cells. Rescue experiments with wt or kinase-dead mutants showed further that BUB1B kinase activity was also required to maintain proliferation of established CRPC cells. While persistent androgen receptor (AR) signaling is a mechanism of CRPC progression, BUB1B promotion of CRPC was not dependent on AR as assessed through AR knockdown. Consistent with an AR-bypass mechanism, ectopic expression of BUB1B rendered PC cells resistant to enzalutamide in vitro and in vivo. Our data points to BUB1B as a key driver of CRPC progression and enzalutamide resistance and suggests that targeting BUB1B kinase is a promising therapeutic approach for lethal, treatment-resistant disease. Statement of significanceWe document a novel role for BUB1B kinase as a critical driver of castration- and enzalutamide-resistant prostate cancer, highlighting the therapeutic potential of BUB1B kinase inhibition to overcome lethal treatment-resistant disease.

cancer biology↗

bioRxiv2024

Pan-Cancer Drug Sensitivity Prediction from Gene Expression using Deep Learning

Cancer is a group of complex diseases, with tumor heterogeneity, durable drug efficacy, emerging resistance, and host toxicity presenting major challenges to the development of effective cancer therapeutics. While traditionally used methods have remained limited in their capacity to overcome these challenges in cancer drug development, efforts have been made in recent years toward applying "big data" to cancer research and precision oncology. By curating, standardizing, and integrating data from various databases, we developed deep learning architectures that use perturbation and baseline transcriptional signatures to predict efficacious small molecule compounds and genetic dependencies in cancer. A series of internal validations followed by prospective validation in prostate cancer cell lines were performed to ensure consistent performance and model applicability. We report SensitivitySeq, a novel bioinformatics tool for prioritizing small molecule compounds and gene dependencies in silico to drive the development of targeted therapies for cancer. To the best of our knowledge, this is the first supervised deep learning approach, validated in vitro, to predict drug sensitivity using baseline cancer cell line gene expression alongside cell line-independent perturbation-response consensus signatures. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=180 SRC="FIGDIR/small/623715v1_ufig1.gif" ALT="Figure 1"> View larger version (73K): org.highwire.dtl.DTLVardef@9f48bcorg.highwire.dtl.DTLVardef@16056f7org.highwire.dtl.DTLVardef@1ed9095org.highwire.dtl.DTLVardef@1af3fce_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2023

Inhibition of the serine/threonine kinase BUB1 reverses taxane resistance in prostate cancer

Background: Men with incurable castration resistant prostate cancer (CRPC) are typically treated with taxanes; however, drug resistance rapidly develops. Thus, overcoming taxane resistant PC is a major clinical need. We previously identified a seven gene network in aggressive CRPC, which includes the mitotic serine threonine kinase BUB1, a major regulator of the spindle assembly checkpoint (SAC). Alterations in mitotic kinases (and SAC malfunction) are associated with advanced PC and taxane resistance development and thereby represent potential vulnerabilities. Methods: We evaluated BUB1 expression in publicly available data sets and in existing and newly generated taxane resistant PC cells. The effects of BUB1 depletion on the growth of a panel of PC and non-tumorigenic prostate epithelial cells was determined. We examined the capacity of pharmacologic inhibition of BUB1 kinase to reverse taxane-resistant PC growth. We evaluated the role of the prevalent androgen receptor variant AR-V7, in regulating BUB1 expression and taxane resistance. Results: BUB1 mRNA was over-expressed in PC, metastatic castration resistant prostate cancer (mCRPC) and in tumors of patients treated with taxane-based chemotherapeutics compared to benign prostate tissue. Furthermore, BUB1 levels were elevated in taxane resistant PC cell lines compared to their sensitive counterparts. BUB1 depletion decreased growth of CRPC cells through delayed mitosis but did not affect proliferation of androgen dependent (ADPC) or non-tumorigenic prostate epithelial cells. Furthermore, BUB1 inhibition with the specific kinase inhibitor, BAY1816032, re-sensitized taxane resistant CRPC cells to the clinically used drugs, docetaxel and cabazitaxel. Consistent with AR-V7 regulation of BUB1, we also found that AR-V7 was elevated in taxane resistant CRPC cells. Moreover, ectopic expression of AR-V7 in CRPC cells that lack this protein resulted in increased BUB1 and conferred docetaxel resistance. BUB1 pharmacologic inhibition in combination with taxanes sensitized AR-V7 expressing CRPC cells to docetaxel treatment. Conclusion: These data support BUB1 as an exploitable and therapeutically tractable vulnerability in taxane resistant CRPC including in AR variant driven CRPC.

cancer biology↗