Systematic screening identifies dual PI3K and mTOR inhibition as a conserved therapeutic vulnerability in osteosarcoma

Journal article


Gupte, Ankita, Baker, E. K., Wan, Soo-San, Stewart, Elizabeth, Loh, Amos, Shelat, Anang A., Gould, Cathryn M., Chalk, Alistair M., Taylor, Scott, Lackovic, Kurt, Karlström, Åsa, Mutsaers, Anthony J., Desai, Jayesh, Madhamshettiwar, Piyush B., Zannettino, Andrew C. W., Burns, Christopher J., Huang, David C. S., Dyer, Michael A., Simpson, Kaylene J. and Walkley, Carl. (2015). Systematic screening identifies dual PI3K and mTOR inhibition as a conserved therapeutic vulnerability in osteosarcoma. Clinical Cancer Research. 21(14), pp. 3216 - 3229. https://doi.org/10.1158/1078-0432.CCR-14-3026
AuthorsGupte, Ankita, Baker, E. K., Wan, Soo-San, Stewart, Elizabeth, Loh, Amos, Shelat, Anang A., Gould, Cathryn M., Chalk, Alistair M., Taylor, Scott, Lackovic, Kurt, Karlström, Åsa, Mutsaers, Anthony J., Desai, Jayesh, Madhamshettiwar, Piyush B., Zannettino, Andrew C. W., Burns, Christopher J., Huang, David C. S., Dyer, Michael A., Simpson, Kaylene J. and Walkley, Carl
Abstract

Purpose: Osteosarcoma is the most common cancer of bone occurring mostly in teenagers. Despite rapid advances in our knowledge of the genetics and cell biology of osteosarcoma, significant improvements in patient survival have not been observed. The identification of effective therapeutics has been largely empirically based. The identification of new therapies and therapeutic targets are urgently needed to enable improved outcomes for osteosarcoma patients.
Experimental Design: We have used genetically engineered murine models of human osteosarcoma in a systematic, genome-wide screen to identify new candidate therapeutic targets. We performed a genome-wide siRNA screen, with or without doxorubicin. In parallel, a screen of therapeutically relevant small molecules was conducted on primary murine– and primary human osteosarcoma–derived cell cultures. All results were validated across independent cell cultures and across human and mouse osteosarcoma.
Results: The results from the genetic and chemical screens significantly overlapped, with a profound enrichment of pathways regulated by PI3K and mTOR pathways. Drugs that concurrently target both PI3K and mTOR were effective at inducing apoptosis in primary osteosarcoma cell cultures in vitro in both human and mouse osteosarcoma, whereas specific PI3K or mTOR inhibitors were not effective. The results were confirmed with siRNA and small molecule approaches. Rationale combinations of specific PI3K and mTOR inhibitors could recapitulate the effect on osteosarcoma cell cultures.
Conclusions: The approaches described here have identified dual inhibition of the PI3K–mTOR pathway as a sensitive, druggable target in osteosarcoma, and provide rationale for translational studies with these agents.

Year2015
JournalClinical Cancer Research
Journal citation21 (14), pp. 3216 - 3229
PublisherAmerican Association for Cancer Research
ISSN1078-0432
Digital Object Identifier (DOI)https://doi.org/10.1158/1078-0432.CCR-14-3026
Scopus EID2-s2.0-84942847123
Page range3216 - 3229
Research GroupMary MacKillop Institute for Health Research
Publisher's version
File Access Level
Controlled
Place of publicationUnited States of America
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Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplsms
Chalk, Alistair M., Liddicoat, Brian J., Walkley, Carl and Singbrant, Sofie. (2014). Gene expression profiling to define the cell intrinsic role of the SKI proto-oncogene in hematopoiesis and myeloid neoplsms. Genomics Data. 2, pp. 189 - 191. https://doi.org/10.1016/j.gdata.2014.06.022
The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories
Carhart-Harris, R. L., Wall, M. B., Erritzoe, D., Kaelen, M., Ferguson, B., De Meer, I., Tanner, M., Bloomfield, M., Williams, T. M., Bolstridge, M., Stewart, L., Morgan, C. J., Newbould, R. D., Feilding, A., Curran, H. V. and Nutt, D. J.. (2014). The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories. International Journal of Neuropsychopharmacology. 17(4), pp. 527 - 540. https://doi.org/10.1017/S1461145713001405
The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease
Singbrant, Sofie, Wall, Meaghan, Moody, Jennifer, Karlsson, Göran, Chalk, Alistair M., Liddicoat, Brian J., Russell, Megan R., Walkley, Carl R. and Karlsson, Stefan. (2014). The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease. Haematologica. 99(4), pp. 647 - 655. https://doi.org/10.3324/haematol.2013.093971
The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis
Smeets, Monique F., DeLuca, Elisabetta, Wall, Meaghan, Quach, Julie M., Chalk, Alistair M., Deans, Andrew J., Heierhorst, Jörg, Purton, Louise E., Izon, David J. and Walkley, Carl R.. (2014). The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis. Journal of Clinical Investigation. 124(8), pp. 3551 - 3565. https://doi.org/10.1172/JCI75334
Cells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells?
Mutsaers, Anthony J. and Walkley, Carl R.. (2014). Cells of origin in osteosarcoma: Mesenchymal stem cells or osteoblast committed cells? Bone. 62, pp. 56 - 63. https://doi.org/10.1016/j.bone.2014.02.003
Immune response to rb1-regulated senescence limits radiation-Induced osteosarcoma formation
Kansara, Maya, Leong, Huei San, Lin, Dan Mei, Popkiss, Sophie, Pang, Puiyi, Garsed, Dale W., Walkley, Carl R., Cullinane, Carleen, Ellul, Jason, Haynes, Nicole M., Hicks, Rod, Kuijjer, Marieke L., Cleton-Jansen, Anne-Marie, Hinds, Philip W., Smyth, Mark J. and Thomas, David M.. (2013). Immune response to rb1-regulated senescence limits radiation-Induced osteosarcoma formation. Journal of Clinical Investigation. 123(12), pp. 5351 - 5360. https://doi.org/10.1172/JCI70559
Erythroid-extrinsic regulation of normal erythropoiesis by retinoic acid receptors
Dewamitta, Sita R., Joseph, Chacko, Purton, Louise E. and Walkley, Carl R.. (2013). Erythroid-extrinsic regulation of normal erythropoiesis by retinoic acid receptors. British Journal of Haematology. 164(2), pp. 280 - 285. https://doi.org/10.1111/bjh.12578
Modeling distinct osteosarcoma subtypes in vivo using Cre: Lox and lineage-restricted transgenic shRNA
Mutsaers, Anthony J., Ng, Alvin J. M., Baker, Emma K., Russell, Megan R., Chalk, Alistair M., Wall, Meaghan, Liddicoat, Brian J. J., Ho, Patricia W. M., Slavin, John L., Goradia, Ankita, Martin, T. John, Purton, Louise E., Dickins, Ross A. and Walkley, Carl R.. (2013). Modeling distinct osteosarcoma subtypes in vivo using Cre: Lox and lineage-restricted transgenic shRNA. Bone. 55(1), pp. 166 - 178. https://doi.org/10.1016/j.bone.2013.02.016
Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment
Dewamitta, Sita R., Russell, Megan R., Nandurkar, Harshal and Walkley, Carl R.. (2013). Darbepoietin-alfa has comparable erythropoietic stimulatory effects to recombinant erythropoietin whilst preserving the bone marrow microenvironment. Haematologica. 98(5), pp. 686 - 690. https://doi.org/10.3324/haematol.2012.078709
Deciphering hematopoietic stem cells in their niches: A critical appraisal of genetic models, lineage tracing, and imaging strategies
Joseph, Chacko, Quach, Julie M., Walkley, Carl R., Lane, Steven W., Celso, Cristina Lo and Purton, Louise E.. (2013). Deciphering hematopoietic stem cells in their niches: A critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell. 13(5), pp. 520 - 533. https://doi.org/10.1016/j.stem.2013.10.010
The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim
Jurado, Sabine, Gleeson, Kimberly, O’Donnell, Kristy, Izon, David J., Walkley, Carl R., Strasser, Andreas, Tarlinton, David M. and Heierhorst, Jörg. (2012). The zinc-finger protein ASCIZ regulates B cell development via DYNLL1 and Bim. Journal of Experimental Medicine. 209(9), pp. 1629-1639. https://doi.org/10.1084/jem.20120785
Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion
Lu, Jiayun, Sun, Yan, Nombela-Arrieta, Cesar, Du, Karrie P., Park, Shin-Young, Chai, Li, Walkley, Carl, Luo, Hongbo R. and Silberstein, Leslie E.. (2012). Fak depletion in both hematopoietic and nonhematopoietic niche cells leads to hematopoietic stem cell expansion. Experimental Hematology. 40(4), pp. 307-317. https://doi.org/10.1016/j.exphem.2011.11.010
Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment
Singbrant, Sofie, Russell, Megan R., Jovic, Tanja, Liddicoat, Brian, Izon, David J., Purton, Louise E., Sims, Natalie A., Martin, T. John, Sankaran, Vijay G. and Walkley, Carl R.. (2011). Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment. Blood. 117(21), pp. 5631-5642. https://doi.org/10.1182/blood-2010-11-320564
Erythropoiesis, anemia and the bone marrow microenvironment
Walkley, Carl R.. (2011). Erythropoiesis, anemia and the bone marrow microenvironment. International Journal of Hematology. 93, pp. 10-13. https://doi.org/10.1007/s12185-010-0759-6
Defining the hematopoietic stem cell niche : The chicken and the egg conundrum
Singbrant, Sofie, Askmyr, Maria, Purton, Louise E. and Walkley, Carl R.. (2011). Defining the hematopoietic stem cell niche : The chicken and the egg conundrum. Journal of Cellular Biochemistry. 112(6), pp. 1486-1490. https://doi.org/10.1002/jcb.23085
Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan, Schertzer, Jonathan, Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl, Izon, David, Honeyman, Jane, Chen, Zhi-Ping, Van Denderen, Bryce, Kemp, Bruce and Steinberg, Gregory. (2011). Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577
Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity
Galic, Sandra, Fullerton, Morgan D., Schertzer, Jonathan D., Sikkema, Sarah, Marcinko, Katarina, Walkley, Carl R., Izon, David, Honeyman, Jane, Chen, Zhi-Ping, van Denderen, Bryce J., Kemp, Bruce Ernest and Steinberg, Gregory R.. (2011). Hematopoietic AMPK Beta ß1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. Journal of Clinical Investigation. 121(12), pp. 4903 - 4915. https://doi.org/10.1172/JCI58577