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Experimental and Molecular Therapeutics

Abstract 2147: Overcoming mTOR resistance mutations with a new generation mTOR inhibitor

Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris Novotny, Claire McWhirter, Arpitha Banaji, Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen and Kevan M. Shokat
Vanessa S. Rodrik-Outmezguine
Memorial Sloan Kettering Cancer Center, New York, NY;
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Masanori Okaniwa
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA;
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Zhan Yao
Memorial Sloan Kettering Cancer Center, New York, NY;
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Chris Novotny
Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA;
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Claire McWhirter
AstraZeneca, Macclesfield, United Kingdom;
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Arpitha Banaji
Memorial Sloan Kettering Cancer Center, New York, NY;
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Helen Won
Memorial Sloan Kettering Cancer Center, New York, NY;
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Wai Wong
Memorial Sloan Kettering Cancer Center, New York, NY;
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Mike Berger
Memorial Sloan Kettering Cancer Center, New York, NY;
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Elisa de Stanchina
Memorial Sloan Kettering Cancer Center, New York, NY;
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Derek G. Barratt
AstraZeneca, Macclesfield, United Kingdom;
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Sabina Cosulich
AstraZeneca, Macclesfield, United Kingdom;
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Teresa Klinowska
AstraZeneca, Macclesfield, United Kingdom;
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Neal Rosen
Memorial Sloan Kettering Cancer Center, New York, NY;
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Kevan M. Shokat
University of California San Francisco, San Francisco, CA.
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DOI: 10.1158/1538-7445.AM2016-2147 Published July 2016
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Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA

Abstract

First generation mTOR inhibitors (rapalogs) have modest activity in some tumors. We sought to delineate the likely resistance mechanisms to existing mTOR inhibitors as a guide for next generation therapies. We identified FRB domain and kinase domain mutations as causing acquired-resistance to rapamycin and mTOR kinase inhibitor respectively.

Resistance to rapamycin was due to loss of binding of the FKBP12-rapamycin complex to the FRB domain of mTOR mutant protein. Resistance to the mTOR kinase inhibitor was not due to a gatekeeper mutation but rather to an increase in the intrinsic kinase activity of the mTOR kinase domain mutant. These and similar mutations have also been identified in tumors from untreated patients. These findings suggest that these mutations are gain of function mutants but also that tumors with these activating mutations will be intrinsically resistant to second generation mTOR kinase inhibitors.

We have designed a new class of mTOR inhibitor, RapaLink-1, that takes advantage of the juxtaposition of two drug binding pockets to create a bivalent interaction. This compound potently inhibits mTOR activation in cells with mTOR wild-type and overcomes resistance to existing first and second generation inhibitors. Moreover, intermittent dosing of RapaLink-1 effectively suppresses mTOR-dependent tumor growth in vivo. Thus, such third generation mTOR inhibitors could be useful for treating tumors with activating mutations of mTOR and for tumors with acquired-resistance to current mTOR inhibitors.[N.R. and K.S. contributed equally to this work.]

Citation Format: Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris Novotny, Claire McWhirter, Arpitha Banaji, Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen, Kevan M. Shokat. Overcoming mTOR resistance mutations with a new generation mTOR inhibitor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2147.

  • ©2016 American Association for Cancer Research.
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Cancer Research: 76 (14 Supplement)
July 2016
Volume 76, Issue 14 Supplement
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Abstract 2147: Overcoming mTOR resistance mutations with a new generation mTOR inhibitor
Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris Novotny, Claire McWhirter, Arpitha Banaji, Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen and Kevan M. Shokat
Cancer Res July 15 2016 (76) (14 Supplement) 2147; DOI: 10.1158/1538-7445.AM2016-2147

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Abstract 2147: Overcoming mTOR resistance mutations with a new generation mTOR inhibitor
Vanessa S. Rodrik-Outmezguine, Masanori Okaniwa, Zhan Yao, Chris Novotny, Claire McWhirter, Arpitha Banaji, Helen Won, Wai Wong, Mike Berger, Elisa de Stanchina, Derek G. Barratt, Sabina Cosulich, Teresa Klinowska, Neal Rosen and Kevan M. Shokat
Cancer Res July 15 2016 (76) (14 Supplement) 2147; DOI: 10.1158/1538-7445.AM2016-2147
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