Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers

Autor: Hannah L. Archibald, Steve Rowley, Faria M. Siddiqui, Sukhvinder Sidhu, Aaron N. Hata, Madelyn Light, Jeffrey A. Engelman, James Watters, Joon Sang Lee, Maria Gomez-Caraballo, Joonil Jung, Laurent Debussche, Ruslan I. Sadreyev, Fei Ji
Rok vydání: 2017
Předmět:
0301 basic medicine
Cancer Research
Indoles
Lung Neoplasms
Cell
Mutant
Apoptosis
medicine.disease_cause
Mice
chemistry.chemical_compound
Carcinoma
Non-Small-Cell Lung
Puma
RNA
Small Interfering
Bcl-2-Like Protein 11
MEK inhibitor
Drug Synergism
Proto-Oncogene Proteins c-mdm2
MAP Kinase Kinase Kinases
medicine.anatomical_structure
Gene Knockdown Techniques
Mdm2
RNA Interference
KRAS
Growth inhibition
Colorectal Neoplasms
Niacinamide
MAP Kinase Signaling System
Mice
Nude
Biology
Article
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
In vivo
Proto-Oncogene Proteins
Genetics
medicine
Animals
Humans
Spiro Compounds
Protein Kinase Inhibitors
neoplasms
Molecular Biology
Cell Proliferation
HCT116 Cells
biology.organism_classification
Xenograft Model Antitumor Assays
030104 developmental biology
chemistry
A549 Cells
Drug Resistance
Neoplasm
Mutation
biology.protein
Cancer research
Tumor Suppressor Protein p53
Apoptosis Regulatory Proteins
Zdroj: Oncogene
ISSN: 1476-5594
0950-9232
DOI: 10.1038/onc.2017.258
Popis: There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.
Databáze: OpenAIRE
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