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Combination of ATP-competitive mammalian target of rapamycin inhibitors with standard chemotherapy for colorectal cancer

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Abstract

ATP-competitive mammalian target of rapamycin (mTOR) inhibitors are in early phase clinical trials. These novel targeted agents, including PP242, are mechanistically distinct from the allosteric, partial mTOR inhibitor, rapamycin. The goal of this study was to evaluate how PP242 best combines with standard chemotherapies for colorectal cancer (CRC), and which subsets of patients are most likely to benefit. The combination index for PP242 plus 5-fluorouracil, oxaliplatin, or irinotecan was determined in CRC cell lines with different mutational backgrounds. In KRAS mutant CRC cell lines, sensitivity to PP242 increases with co-mutation of PIK3CA. Mutation of p53 predicts resistance to chemotherapy, but not PP242. Efficacy of PP242 was comparable to that of standard chemotherapies over the dose range tested. Sensitivity or resistance to PP242 dictates relative synergy or antagonism, respectively, when PP242 is combined with 5-fluorouracil. The same trend exists for PP242 + oxaliplatin, but with a narrower dynamic range. Conversely potency of PP242 and the combination index for PP242 + irinotecan were unrelated, but synergy exists across all dose levels in PP242 and irinotecan sensitive, p53 wild-type cell lines. Overall, our in vitro analysis predicts that mutational status can be used to rank sensitivity to PP242 and standard chemotherapies. Single agent potency can in turn be used to predict the combination index in a drug-specific manner. Our data suggest a clinical trial to determine whether ATP-competitive mTOR inhibitors provide benefit in combination with standard chemotherapies for patients with PIK3CA mutant metastatic CRC, stratified by the presence or absence of KRAS co-mutation.

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Abbreviations

mTOR:

mammalian target of rapamycin

CRC:

colorectal cancer

PI3K:

phosphoinositide 3-kinase

PIK3CA:

gene encoding the PI3K protein

EGFR:

epidermal growth factor receptor

4EBP1:

eukaryotic initiation factor 4E-binding protein-1

CI:

combination index

Fa:

fraction affected

Fu:

fraction unaffected

DMSO:

dimethyl sulfoxide

5FU:

5-fluorouracil

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Acknowledgements

We are grateful to David Donner for editorial assistance and to Yi Liu, Pingda Ren, Christian Rommel, and Katti Jessen at Intellikine for helpful discussions.

Grant support

Funding was provided by a Conquer Cancer Foundation of the American Society of Clinical Oncology Young Investigator Award and the American Cancer Society Postdoctoral Fellowship 11-183-01-TBG (C.E.A) as well as the Howard Hughes Medical Institute (K.M.S.)

Disclosures

K.M.S. is a co-founder of Intellikine and serves on the Scientific Advisory Board.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, UCSF Comprehensive Cancer Center, University of California, 1600 Divisadero Street, 4th Floor, San Francisco, CA, 94115, USA

    Chloe E. Atreya & Emily K. Bergsland

  2. Department of Chemistry, University of California, Berkeley, CA, USA

    Gregory S. Ducker & Kevan M. Shokat

  3. Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA

    Morris E. Feldman & Kevan M. Shokat

  4. Division of Surgical Oncology, University of California, San Francisco, CA, USA

    Robert S. Warren

Authors
  1. Chloe E. Atreya
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  2. Gregory S. Ducker
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  4. Emily K. Bergsland
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Correspondence to Chloe E. Atreya.

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Atreya, C.E., Ducker, G.S., Feldman, M.E. et al. Combination of ATP-competitive mammalian target of rapamycin inhibitors with standard chemotherapy for colorectal cancer. Invest New Drugs 30, 2219–2225 (2012). https://doi.org/10.1007/s10637-012-9793-y

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  • DOI: https://doi.org/10.1007/s10637-012-9793-y

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