PMID- 28436422
OWN - NLM
STAT- MEDLINE
DCOM- 20190711
LR  - 20240210
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 7
DP  - 2017 Apr 24
TI  - Rational design of non-resistant targeted cancer therapies.
PG  - 46632
LID - 10.1038/srep46632 [doi]
LID - 46632
AB  - Drug resistance is one of the major problems in targeted cancer therapy. A major 
      cause of resistance is changes in the amino acids that form the drug-target 
      binding site. Despite of the numerous efforts made to individually understand and 
      overcome these mutations, there is a lack of comprehensive analysis of the 
      mutational landscape that can prospectively estimate drug-resistance mutations. 
      Here we describe and computationally validate a framework that combines the 
      cancer-specific likelihood with the resistance impact to enable the detection of 
      single point mutations with the highest chance to be responsible of resistance to 
      a particular targeted cancer therapy. Moreover, for these treatment-threatening 
      mutations, the model proposes alternative therapies overcoming the resistance. We 
      exemplified the applicability of the model using EGFR-gefitinib treatment for 
      Lung Adenocarcinoma (LUAD) and Lung Squamous Cell Cancer (LSCC) and the 
      ERK2-VTX11e treatment for melanoma and colorectal cancer. Our model correctly 
      identified the phenotype known resistance mutations, including the classic 
      EGFR-T790M and the ERK2-P58L/S/T mutations. Moreover, the model predicted new 
      previously undescribed mutations as potentially responsible of drug resistance. 
      Finally, we provided a map of the predicted sensitivity of alternative ERK2 and 
      EGFR inhibitors, with a particular highlight of two molecules with a low 
      predicted resistance impact.
FAU - Martinez-Jimenez, Francisco
AU  - Martinez-Jimenez F
AD  - CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and 
      Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain.
AD  - Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation 
      (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain.
AD  - Universitat Pompeu Fabra (UPF), Barcelona, Spain.
FAU - Overington, John P
AU  - Overington JP
AD  - Medicines Discovery Catapult Block 35, Mereside, Alderley Park, Alderley Edge, 
      Cheshire, SK10 4TG, UK.
FAU - Al-Lazikani, Bissan
AU  - Al-Lazikani B
AD  - The Institute of Cancer Research, London, UK.
FAU - Marti-Renom, Marc A
AU  - Marti-Renom MA
AD  - CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and 
      Technology (BIST), Baldiri i Reixac 4, 08028 Barcelona, Spain.
AD  - Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation 
      (CRG), Dr. Aiguader 88, 08003 Barcelona, Spain.
AD  - Universitat Pompeu Fabra (UPF), Barcelona, Spain.
AD  - ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain.
LA  - eng
GR  - 11566/CRUK_/Cancer Research UK/United Kingdom
GR  - 22897/CRUK_/Cancer Research UK/United Kingdom
GR  - 23187/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170424
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Neoplasm Proteins)
RN  - S65743JHBS (Gefitinib)
SB  - IM
MH  - *Adenocarcinoma of Lung/drug therapy/genetics/metabolism/pathology
MH  - Antineoplastic Agents/*therapeutic use
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/metabolism/pathology
MH  - Drug Delivery Systems/*methods
MH  - Gefitinib/*therapeutic use
MH  - Humans
MH  - *Lung Neoplasms/drug therapy/genetics/metabolism/pathology
MH  - *Models, Biological
MH  - Neoplasm Proteins/genetics/metabolism
MH  - *Point Mutation
PMC - PMC5402386
COIS- The authors declare no competing financial interests.
EDAT- 2017/04/25 06:00
MHDA- 2019/07/12 06:00
PMCR- 2017/04/24
CRDT- 2017/04/25 06:00
PHST- 2016/11/30 00:00 [received]
PHST- 2017/03/22 00:00 [accepted]
PHST- 2017/04/25 06:00 [entrez]
PHST- 2017/04/25 06:00 [pubmed]
PHST- 2019/07/12 06:00 [medline]
PHST- 2017/04/24 00:00 [pmc-release]
AID - srep46632 [pii]
AID - 10.1038/srep46632 [doi]
PST - epublish
SO  - Sci Rep. 2017 Apr 24;7:46632. doi: 10.1038/srep46632.