Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer.

CRC Combination Therapy Genomic Biomarker PDX

Journal

Gastroenterology

ISSN: 1528-0012

Titre abrégé: Gastroenterology

Pays: United States

ID NLM: 0374630

Informations de publication

Date de publication:
07 2021

Historique:

received: 24 06 2020

revised: 24 02 2021

accepted: 05 03 2021

pubmed: 23 3 2021

medline: 26 10 2021

entrez: 22 3 2021

Statut: ppublish

Résumé

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. 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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1053/j.gastro.2021.03.022 PMID: 33745946 PMC: PMC8238881

pubmed: 33745946

pii: S0016-5085(21)00530-8

doi: 10.1053/j.gastro.2021.03.022

pmc: PMC8238881

mid: NIHMS1685135

pii:

doi:

Substances chimiques

Biomarkers, Tumor 0

Indoles 0

Karyopherins 0

Morpholines 0

Piperazines 0

Protein Kinase Inhibitors 0

Pyridines 0

Pyrimidines 0

Receptors, Cytoplasmic and Nuclear 0

Sulfonamides 0

TP53 protein, human 0

Tumor Suppressor Protein p53 0

ceralasertib 85RE35306Z

ATR protein, human EC 2.7.11.1

Ataxia Telangiectasia Mutated Proteins EC 2.7.11.1

palbociclib G9ZF61LE7G

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

196-210

Subventions

Organisme : NCI NIH HHS

ID : P30 CA016672

Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

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