PMID- 22270257
OWN - NLM
STAT- MEDLINE
DCOM- 20130404
LR  - 20211203
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 30
IP  - 6
DP  - 2012 Dec
TI  - Combination of ATP-competitive mammalian target of rapamycin inhibitors with 
      standard chemotherapy for colorectal cancer.
PG  - 2219-25
LID - 10.1007/s10637-012-9793-y [doi]
AB  - 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.
FAU - Atreya, Chloe E
AU  - Atreya CE
AD  - Division of Hematology/Oncology, UCSF Comprehensive Cancer Center, University of 
      California, San Francisco, CA 94115, USA. chloe.atreya@gmail.com
FAU - Ducker, Gregory S
AU  - Ducker GS
FAU - Feldman, Morris E
AU  - Feldman ME
FAU - Bergsland, Emily K
AU  - Bergsland EK
FAU - Warren, Robert S
AU  - Warren RS
FAU - Shokat, Kevan M
AU  - Shokat KM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120124
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Drug Combinations)
RN  - 0 (Indoles)
RN  - 0 (KRAS protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Organoplatinum Compounds)
RN  - 0 (PI3KCA protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Purines)
RN  - 0 (Transcription Factors)
RN  - 04ZR38536J (Oxaliplatin)
RN  - 7673326042 (Irinotecan)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
RN  - H5669VNZ7V (PP242)
RN  - U3P01618RT (Fluorouracil)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
MH  - Adenosine Triphosphate
MH  - Antineoplastic Agents/*administration & dosage
MH  - Camptothecin/administration & dosage/*analogs & derivatives
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Colorectal Neoplasms/drug therapy/genetics
MH  - Drug Combinations
MH  - Fluorouracil/*administration & dosage
MH  - Humans
MH  - Indoles/*administration & dosage
MH  - Irinotecan
MH  - Mutation
MH  - Nuclear Proteins/genetics
MH  - Organoplatinum Compounds/*administration & dosage
MH  - Oxaliplatin
MH  - Proto-Oncogene Proteins/genetics
MH  - Proto-Oncogene Proteins p21(ras)
MH  - Purines/*administration & dosage
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Transcription Factors/genetics
MH  - ras Proteins/genetics
EDAT- 2012/01/25 06:00
MHDA- 2013/04/05 06:00
CRDT- 2012/01/25 06:00
PHST- 2011/11/04 00:00 [received]
PHST- 2012/01/09 00:00 [accepted]
PHST- 2012/01/25 06:00 [entrez]
PHST- 2012/01/25 06:00 [pubmed]
PHST- 2013/04/05 06:00 [medline]
AID - 10.1007/s10637-012-9793-y [doi]
PST - ppublish
SO  - Invest New Drugs. 2012 Dec;30(6):2219-25. doi: 10.1007/s10637-012-9793-y. Epub 
      2012 Jan 24.