Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3

Autor: Federica Di Nicolantonio, Pasi Halonen, Wipawadee Grernrum, Alberto Bardelli, Davide Zecchin, Cor Lieftink, Roderick L. Beijersbergen, Lodewyk F. A. Wessels, Livio Trusolino, Anna Tzani, Anirudh Prahallad, Francesca Cottino, Egbert F. Smit, Andreas Schlicker, Chong Sun, Sebastijan Hobor, Francesco Galimi, Andrea Bertotti, Sidong Huang, Erik Thunnissen, René Bernards
Přispěvatelé: Pulmonary medicine, Pathology, CCA - Oncogenesis
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Lung Neoplasms
Receptor
ErbB-3
Receptor
ErbB-2
MYC PROTEIN STABILITY
DRUG-SENSITIVITY
RAS ONCOGENES
C-MYC
KINASE
PHOSPHORYLATION
MELANOMA
RECEPTOR
BRAF
Mutant
Apoptosis
Synthetic lethality
medicine.disease_cause
Receptor tyrosine kinase
Mice
0302 clinical medicine
ERBB3
RNA
Small Interfering
lcsh:QH301-705.5
0303 health sciences
biology
Kinase
Melanoma
Drug Synergism
MAP Kinase Kinase Kinases
3. Good health
ErbB Receptors
030220 oncology & carcinogenesis
Colonic Neoplasms
KRAS
Mice
Nude
General Biochemistry
Genetics and Molecular Biology
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Downregulation and upregulation
Cell Line
Tumor
Proto-Oncogene Proteins
medicine
Animals
Humans
Protein Kinase Inhibitors
030304 developmental biology
medicine.disease
Xenograft Model Antitumor Assays
lcsh:Biology (General)
Mutation
ras Proteins
biology.protein
Cancer research
Zdroj: Cell Reports, Vol 7, Iss 1, Pp 86-93 (2014)
Cell Reports, 7(1), 86-93. Cell Press
Sun, C, Hobor, S, Bertotti, A, Zecchin, D, Huang, S D, Galimi, F, Cottino, F, Prahallad, A, Grernrum, W, Tzani, A, Schlicker, A, Wessels, L F A, Smit, E F, Thunnissen, E, Halonen, P, Lieftink, C, Beijersbergen, R L, Di Nicolantonio, F, Bardelli, A, Trusolino, L & Bernards, R 2014, ' Intrinsic Resistance to MEK Inhibition in KRAS Mutant Lung and Colon Cancer through Transcriptional Induction of ERBB3 ', Cell Reports, vol. 7, no. 1, pp. 86-93 . https://doi.org/10.1016/j.celrep.2014.02.045
ISSN: 2211-1247
Popis: SummaryThere are no effective therapies for the ∼30% of human malignancies with mutant RAS oncogenes. Using a kinome-centered synthetic lethality screen, we find that suppression of the ERBB3 receptor tyrosine kinase sensitizes KRAS mutant lung and colon cancer cells to MEK inhibitors. We show that MEK inhibition results in MYC-dependent transcriptional upregulation of ERBB3, which is responsible for intrinsic drug resistance. Drugs targeting both EGFR and ERBB2, each capable of forming heterodimers with ERBB3, can reverse unresponsiveness to MEK inhibition by decreasing inhibitory phosphorylation of the proapoptotic proteins BAD and BIM. Moreover, ERBB3 protein level is a biomarker of response to combinatorial treatment. These data suggest a combination strategy for treating KRAS mutant colon and lung cancers and a way to identify the tumors that are most likely to benefit from such combinatorial treatment.
Databáze: OpenAIRE
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