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1. Table S2 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

93 gene signature that characterizes ZFTA-Rela mouse and human tumors.

Published
2023

2. Table S6 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

DNA motifs detected and shared with mouse embryonic fibroblasts treated with TNF-alpha

Published
2023

3. Figure S2 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Figure S2 supporting expression and localization of ZRfus in the mouse IUE model.

Published
2023

4. Table S8 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

CRCs detected in mouse IUE ZRfus1 driven ependymoma

Published
2023

5. Table S7 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Super enhancers detected in IUE ZRfus1 model

Published
2023

6. Figure S6 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Figure S6 to show up-regulation of the NF-kB pathway in ZRfus IUE tumors

Published
2023

7. Table S1 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Differential gene expression between mouse IUE:ZRfus1 and mouse normal brain

Published
2023

8. Table S9 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Summary of oligos and sgRNA sequences used in the study

Published
2023

9. Table S3 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

HA-ZRfus1 bound and over-expressed genes compared to mouse normal brain

Published
2023

10. Data from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.Significance:Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA–RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.This article is highlighted in the In This Issue feature, p. 2113

Published
2023

11. Table S5 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

DNA motifs detected specifically in mouse IUE ZRfus1 tumors

Published
2023

12. Figure S1 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Figure S1 to show differential genes expressed in ZRfus tumors vs normal brain.

Published
2023

13. Table S4 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Differentially expressed genes Between non-targeting control and Rela KO in IUE ZRfus1 model

Published
2023

14. Figure S3 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Figure S3 demonstrating transcriptional alterations as a result of ZRfus loss of function

Published
2023

15. Figure S4 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma

Author

Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade

Abstract

Figure S4 to show supporting data of DNA motif finding in ZRfus specific binding sites.

Published
2023

16. Abstract 1771: Targeting oncogenic transcription in prostate cancer with a novel, oral bioavailable, and ultra-selective CDK9 inhibitor

Author

Christopher Wilfong, André Richters, Angela N. Koehler, Charles Y. Lin, Christina O. Lee, Becky S Leifer, Sajjeev Jagannathan, Doug Saffran, Joseph Vacca, Kristen L. Karlin, Norbert Bischofberger, Jost Vrabic Koren, Shelby K. Doyle, David B. Freeman, Florian Kabinger, Calla M. Olson, Peter J. Mikochik, and Marius S. Pop

Subjects
Androgen receptor, Cancer Research, Oncology, biology, Transcription (biology), Cyclin-dependent kinase, Kinase, Gene expression, Cancer research, biology.protein, RNA polymerase II, Cell cycle, Transcription factor
Abstract

Castration resistant prostate cancers (CRPCs) lose sensitivity to hormone therapy, but remain dependent on oncogenic transcription programs driven by the androgen receptor (AR) and other oncogenic transcription factors such as MYC. Using small molecule microarrays (SMMs), we screened HEK293 cellular lysates for compounds binding to exogenously expressed ARv7, a mutant splice form of AR that drives castration resistance. Although transcription factors like ARv7 and MYC are considered classically undruggable, SMMs are able to identify small molecule interactors of druggable co-factors and other proteins in complex with the target protein – in this case ARv7. SMM hits were triaged for the ability to selectively inhibit an AR dependent transcriptional reporter, and also for their ability to reduce proliferation in AR dependent tumor cells. From this screen, we identified KI-ARv3, a potent and selective inhibitor of CDK9. CDK9 is a cyclin-dependent kinase (CDK) that functions primarily as a general co-factor in RNA Polymerase II (RNA Pol II) transcription elongation. CDK9 is a well-characterized and important cofactor for AR, MYC, and other oncogenic transcription factors. In prostate cancer, CDK9 has been shown to modulate and be required for AR-specific gene expression. More broadly, transcriptional CDK inhibitors including those selective for CDK9 have shown strong potential as therapeutic agents owing to their ability to selectively downregulate oncogenic transcription programs and target tumors addicted to transcription factors such as AR or MYC. However, as CDK9 also plays a global role in transcription, it is unclear whether there exists a sufficient therapeutic index for clinical benefit. Prior clinical investigation of transcriptional CDK inhibitors has also been confounded by off-target interactions with other kinases and especially other CDKs that also play important roles in transcription and the cell cycle. We found that KI-ARv3 demonstrated excellent selectivity for CDK9 versus other CDKs and kinases, and further optimization of KI-ARv3 resulted in KB-00130742, an oral bioavailable CDK9 inhibitor with a biochemical IC50 of 15nM against CDK9 and greater than 50-fold selectivity for all profiled CDKs and greater than 100-fold selectivity against cell cycle CDKs. Both KI-ARv3 and KB-00130742 exhibited potent anti-tumor activity in CRPC models, as well as other models known to be dependent on MYC-driven transcription. In 22Rv1 CRPC cells, KB-00130742 rapidly downregulated nascent transcription, and preferentially depleted short half-life transcripts and AR driven oncogenic programs. In vivo, oral administration of KB-00130742 was well-tolerated and significantly reduced tumor growth in models of CRPC and leukemia. Overall these data support CDK9 inhibition using KB-00130742 as a therapeutic strategy to target AR dependence in CRPC and oncogenic transcription in other tumor types. Citation Format: André Richters, David Freeman, Christina Lee, Florian Kabinger, Shelby Doyle, Becky Leifer, Peter Mikochik, Sajjeev Jagannathan, Jost Vrabic Koren, Kristen Karlin, Calla M. Olson, Christopher Wilfong, Charles Y. Lin, Doug Saffran, Joseph Vacca, Norbert Bischofberger, Marius Pop, Angela N. Koehler. Targeting oncogenic transcription in prostate cancer with a novel, oral bioavailable, and ultra-selective CDK9 inhibitor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1771.

Published
2020

17. Abstract P6-11-01: A broad spectrum therapeutic strategy for TNBC revealed by a new pathway that coordinates oncogenic RTKs

Author

Noah Dephoure, Susan G. Hilsenbeck, Thomas F. Westbrook, Richard A. Gibbs, Chad J. Creighton, Stephen J. Elledge, C. Kent Osborne, James G. Christensen, David J. Shields, Rachel Schiff, Jessica D. Kessler, Amritha Nair, Kristen L. Karlin, Chad A. Shaw, David A. Wheeler, Tingting Sun, Alex Renwick, Steven P. Gygi, Don X. Nguyen, Michael T. Lewis, I. Migliaccio, and Ronald J. Bernardi

Subjects
Genetics, Cancer Research, biology, Genetic heterogeneity, business.industry, Cancer, Protein tyrosine phosphatase, medicine.disease, Receptor tyrosine kinase, law.invention, Breast cancer, Oncology, law, biology.protein, Cancer research, Suppressor, Medicine, business, Tyrosine kinase, Genetic screen
Abstract

Triple-negative breast cancer (TNBC) is a collection of diseases with distinct clinical behaviors and heterogeneous molecular features. Such clinical and genetic heterogeneity has called into question whether there are common pathogenic mechanisms (and potential therapeutic targets) driving the TNBC subtype of breast cancer. Herein, we present evidence of a novel tumor suppressor network that is frequently compromised in TNBC, and a broadly-effective strategy to target this pathway for TNBC therapeutic intervention. Using an unbiased genetic screen, we identified a tumor suppressor network governing tumor survival of TNBCs in vitro and in vivo. We define the tyrosine phosphatase PTPN12 as a core component in this network. PTPN12 is a potent suppressor of mammary epithelial cell survival and transformation, and PTPN12 function is compromised in more than 70% of human TNBCs. Notably, the tumorigenic and metastatic potential of PTPN12-deficient TNBCs is severely impaired by restoring PTPN12, suggesting that strategies to mimic PTPN12 function have substantive therapeutic potential. Using integrative proteomic, genetic, and pharmacologic approaches, we demonstrate that PTPN12 suppresses TNBC survival by inhibiting multiple oncogenic receptor tyrosine kinases (TKs) including MET, PDGFRβ, and others. Frequent inactivation of PTPN12 in human TNBC unleashes these oncogenic TKs in a concerted manner. Importantly, combination inhibitors targeting these PTPN12-regulated TKs significantly impair TNBC cell survival and confer robust tumor regression across a panel of 18 patient-derived xenograft ("PDX") models of human TNBC. This suggests that TNBCs are broadly dependent on a distinct combination of proto-oncogenic tyrosine kinases constrained by PTPN12. Collectively, these data identify PTPN12 as a commonly inactivated tumor suppressor in TNBC and provide a rationale for combinatorially targeting select receptor tyrosine kinases in TNBC and other cancers based on their defects in tyrosine phosphatase activity. Citation Format: Thomas F Westbrook, Amritha Nair, Tingting Sun, Kristen L Karlin, Jessica Kessler, Ilenia Migliaccio, Don X Nguyen, Ronald J Bernardi, Alex Renwick, Chad J Creighton, Noah Dephoure, Steven P Gygi, Chad A Shaw, Richard Gibbs, David Wheeler, Rachel Schiff, James G Christensen, David J Shields, C Kent Osborne, Stephen J Elledge, Susan G Hilsenbeck, Michael T Lewis. A broad spectrum therapeutic strategy for TNBC revealed by a new pathway that coordinates oncogenic RTKs [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-01.

Published
2015

18. Abstract PR02: The spliceosome is a therapeutic vulnerability in MYC-driven breast cancer

Author

Nicholas J. Neill, Thomas A. Cooper, Chad A. Shaw, Chandraiah Lagisetti, Lukas M. Simon, Thomas R. Webb, Tiffany Y.T. Hsu, Thomas F. Westbrook, Azin Sayad, Benjamin G. Neel, Richard Marcotte, and Kristen L. Karlin

Subjects
Cancer Research, Spliceosome, Hyperactivation, Oncogene, Cell, Intron, Cancer, Biology, medicine.disease, medicine.anatomical_structure, Breast cancer, Oncology, RNA splicing, Cancer research, medicine, Molecular Biology
Abstract

c-MYC (MYC) hyperactivation is one of the most common drivers of human breast cancer and correlates with poor prognosis. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto breast cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We demonstrate that core components of the spliceosome and its catalytic activity are required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces global changes in mRNA metabolism and increases the burden on the core spliceosome to process pre-mRNA. In primary human breast cancers, MYC hyperactivation is associated with altered splicing efficiency. In contrast to normal mammary epithelium, partial inhibition of the spliceosome in MYC-hyperactivated breast cancers leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome are therapeutic entry points for aggressive MYC-driven breast cancers. Citation Format: Tiffany Hsu, Lukas Simon, Nicholas Neill, richard marcotte, Azin Sayad, Kristen Karlin, Chandraiah Lagisetti, Thomas Cooper, Thomas Webb, Benjamin Neel, Chad Shaw, Thomas (“Trey”) Westbrook. The spliceosome is a therapeutic vulnerability in MYC-driven breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr PR02.

Published
2016

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