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Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer
- Source :
- Gastroenterology. 161(1)
- Publication Year :
- 2020
-
Abstract
- Background & Aims Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer. Methods To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC. Results Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC. Conclusions Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.
- Subjects :
- 0301 basic medicine
Indoles
Combination therapy
Colorectal cancer
Pyridines
Morpholines
Receptors, Cytoplasmic and Nuclear
Ataxia Telangiectasia Mutated Proteins
Karyopherins
Piperazines
Transcriptome
03 medical and health sciences
Mice
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Databases, Genetic
Biomarkers, Tumor
Medicine
Animals
Humans
Epidermal growth factor receptor
neoplasms
Protein Kinase Inhibitors
Sulfonamides
Hepatology
biology
business.industry
Gastroenterology
Cancer
G2-M DNA damage checkpoint
medicine.disease
HCT116 Cells
Xenograft Model Antitumor Assays
030104 developmental biology
Pyrimidines
Mutation
Cancer research
biology.protein
030211 gastroenterology & hepatology
Tumor Suppressor Protein p53
business
Colorectal Neoplasms
Functional genomics
Ataxia telangiectasia and Rad3 related
HT29 Cells
Subjects
Details
- ISSN :
- 15280012
- Volume :
- 161
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Gastroenterology
- Accession number :
- edsair.doi.dedup.....1f698b264050723f59e7b5f4cf101237