Rational design of non-resistant targeted cancer therapies.
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Embargo End Date
ICR Authors
Authors
Martínez-Jiménez, F
Overington, JP
Al-Lazikani, B
Marti-Renom, MA
Overington, JP
Al-Lazikani, B
Marti-Renom, MA
Document Type
Journal Article
Date
2017-04-24
Date Accepted
2017-03-22
Abstract
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.
Citation
Scientific reports, 2017, 7 pp. 46632 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2045-2322
eISSN
2045-2322
Collections
Research Team
Computational Biology and Chemogenomics