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.
Original language | English (US) |
---|---|
Pages (from-to) | 196-210 |
Number of pages | 15 |
Journal | Gastroenterology |
Volume | 161 |
Issue number | 1 |
DOIs | |
State | Published - Jul 2021 |
Keywords
- Combination Therapy
- CRC
- Genomic Biomarker
- PDX
ASJC Scopus subject areas
- Hepatology
- Gastroenterology
MD Anderson CCSG core facilities
- Functional Proteomics Reverse Phase Protein Array Core
- Bioinformatics Shared Resource
- Research Animal Support Facility
- Flow Cytometry and Cellular Imaging Facility
- Advanced Technology Genomics Core
- Cytogenetics and Cell Authentication Core
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In: Gastroenterology, Vol. 161, No. 1, 07.2021, p. 196-210.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer
AU - Inoue, Akira
AU - Robinson, Frederick S.
AU - Minelli, Rosalba
AU - Tomihara, Hideo
AU - Rizi, Bahar Salimian
AU - Rose, Johnathon L.
AU - Kodama, Takahiro
AU - Srinivasan, Sanjana
AU - Harris, Angela L.
AU - Zuniga, Andy M.
AU - Mullinax, Robert A.
AU - Ma, Xiaoyan
AU - Seth, Sahil
AU - Daniele, Joseph R.
AU - Peoples, Michael D.
AU - Loponte, Sara
AU - Akdemir, Kadir C.
AU - Khor, Tin Oo
AU - Feng, Ningping
AU - Roszik, Jason
AU - Sobieski, Mary M.
AU - Brunell, David
AU - Stephan, Clifford
AU - Giuliani, Virginia
AU - Deem, Angela K.
AU - Shingu, Takashi
AU - Deribe, Yonathan Lissanu
AU - Menter, David G.
AU - Heffernan, Timothy P.
AU - Viale, Andrea
AU - Bristow, Christopher A.
AU - Kopetz, Scott
AU - Draetta, Giulio F.
AU - Genovese, Giannicola
AU - Carugo, Alessandro
N1 - Funding Information: Funding Giulio F. Draetta was supported by the Sewell Family Chair in Genomic Medicine. Alessandro Carugo was supported by the MD Anderson Cancer Moon Shots Program and the Fondazione Italiana per la Ricerca sul Cancro (FIRC)-Associazione Italiana per la Ricerca sul Cancro (AIRC) fellowship. Giannicola Genovese was supported by the Cancer Prevention & Research Institute of Texas (CPRIT) Grant RP170722. Sanjana Srinivasan was supported by the CPRIT Research Training Grant (RP170067). Johnathon L. Rose was supported by the Paula-Altman Goldstein fellowship. The research was supported by The MD Anderson Cancer Center (MDACC) (Cancer Center Support Grant, CA016672). The Gulf Coast Consortia (GCC) High Throughput Screening Program was supported by CPRIT Grant RP150578. Funding Information: We wish to thank the members of Viale, Draetta, Genovese, and Carugo laboratories for discussions and reagents. Special thanks to Dr Maria Emilia Di Francesco, Dr Christopher Carroll, and the Institute for Applied Cancer Science (IACS) platform for advice and reagents. We thank the University of Texas MD Anderson Cancer Center (UTMDACC) Department of Veterinary Medicine, the UTMDACC Sequencing & Non-coding RNA Program, and the UTMDACC Flow Facility. Data are provided as supplementary tables. Akira Inoue, MD, PhD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Project administration: Lead; Validation: Lead; Writing ? original draft: Lead; Writing ? review & editing: Lead). Frederick S. Robinson (Data curation: Lead; Formal analysis: Supporting; Investigation: Equal; Methodology: Lead; Project administration: Lead; Validation: Supporting; Writing ? original draft: Supporting; Writing ? review & editing: Supporting). Rosalba Minelli, PhD (Investigation: Equal). Hideo Tomihara, MD, PhD (Data curation: Supporting; Formal analysis: Supporting; Project administration: Supporting; Supervision: Supporting). Bahar Salimian Rizi, PhD (Conceptualization: Supporting; Data curation: Supporting; Project administration: Supporting; Supervision: Supporting). Johnathon L. Rose (Conceptualization: Supporting; Data curation: Supporting; Methodology: Supporting; Project administration: Supporting; Supervision: Supporting). Takahiro Kodama, MD PhD (Investigation: Supporting). Sanjana Srinivasan, Graduate Research Assistant (Data curation: Supporting; Methodology: Supporting; Visualization: Supporting). Angela L. Harris, (Data curation: Equal; Investigation: Equal; Project administration: Equal). Andy M. Zuniga (Data curation: Supporting; Formal analysis: Supporting; Methodology: Supporting; Project administration: Supporting). Robert A. Mullinax, PhD (Conceptualization: Supporting; Formal analysis: Supporting; Funding acquisition: Supporting). Xiaoyan Ma, PhD (Data curation: Supporting; Project administration: Supporting). Sahil Seth, PhD (Conceptualization: Equal; Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Methodology: Equal; Project administration: Supporting; Supervision: Supporting). Joseph R. Daniele, PhD (Investigation: Supporting). Michael D. Peoples (Methodology: Supporting; Project administration: Supporting). Sara Loponte, PhD (Data curation: Equal; Formal analysis: Equal; Funding acquisition: Supporting; Investigation: Supporting; Methodology: Supporting; Project. administration: Supporting). Kadir C. Akdemir, PhD (Conceptualization: Supporting; Data curation: Equal; Investigation: Equal; Project administration: Supporting). Tin Oo Khor, PhD (Data curation: Equal; Methodology: Supporting; Project administration: Supporting). Ningping Feng, PhD (Data curation: Equal; Investigation: Supporting; Project administration: Supporting). Jason Roszik, PhD (Conceptualization: Supporting; Data curation: Supporting; Investigation: Supporting; Methodology: Supporting). Mary M. Sobieski (Data curation: Supporting; Investigation: Supporting; Project administration: Supporting). David Brunell, PhD (Conceptualization: Supporting; Data curation: Equal; Methodology: Equal). Clifford Stephan, PhD (Data curation: Supporting; Funding acquisition: Supporting; Investigation: Supporting; Project administration: Supporting; Resources: Supporting; Writing ? review & editing: Supporting). Virginia Giuliani, PhD (Conceptualization: Supporting; Data curation: Supporting; Funding acquisition: Supporting; Investigation: Supporting; Methodology: Supporting; Project administration: Supporting; Supervision: Supporting). Angela K. Deem, PhD (Conceptualization: Supporting; Funding acquisition: Supporting; Supervision: Supporting; Writing ? original draft: Supporting; Writing ? review & editing: Supporting). Takashi Shingu, MD, PhD (Data curation: Supporting; Formal analysis: Supporting; Methodology: Supporting). Yonathan Lissanu Deribe, MD, PhD (Conceptualization: Supporting; Supervision: Supporting). David G. Menter, PhD (Conceptualization: Supporting; Investigation: Supporting; Project administration: Supporting; Supervision: Supporting). Timothy P. Heffernan, PhD (Conceptualization: Lead; Data curation: Supporting; Funding acquisition: Lead; Investigation: Supporting; Supervision: Supporting; Visualization: Supporting). Andrea Viale, MD, PhD (Conceptualization: Supporting; Investigation: Supporting; Supervision: Supporting). Christopher A. Bristow, PhD (Conceptualization: Lead; Data curation: Supporting; Funding acquisition: Supporting; Investigation: Supporting; Methodology: Supporting; Supervision: Supporting; Validation: Supporting). Scott Kopetz, MD, PhD (Conceptualization: Supporting; Data curation: Equal; Funding acquisition: Supporting; Investigation: Supporting; Supervision: Supporting). Giulio F. Draetta, MD, PhD (Conceptualization: Lead; Funding acquisition: Lead; Investigation: Lead; Project administration: Supporting; Supervision: Equal; Validation: Equal). Giannicola Genovese, MD, PhD (Conceptualization: Supporting; Data curation: Supporting; Investigation: Supporting; Methodology: Supporting; Supervision: Supporting). Alessandro Carugo, PhD (Conceptualization: Supporting; Data curation: Supporting; Formal analysis: Supporting; Funding acquisition: Supporting; Investigation: Supporting; Methodology: Supporting; Project administration: Supporting; Supervision: Supporting; Validation: Supporting; Visualization: Supporting; Writing ? original draft: Equal; Writing ? review & editing: Supporting). Funding Giulio F. Draetta was supported by the Sewell Family Chair in Genomic Medicine. Alessandro Carugo was supported by the MD Anderson Cancer Moon Shots Program and the Fondazione Italiana per la Ricerca sul Cancro (FIRC)-Associazione Italiana per la Ricerca sul Cancro (AIRC) fellowship. Giannicola Genovese was supported by the Cancer Prevention & Research Institute of Texas (CPRIT) Grant RP170722. Sanjana Srinivasan was supported by the CPRIT Research Training Grant (RP170067). Johnathon L. Rose was supported by the Paula-Altman Goldstein fellowship. The research was supported by The MD Anderson Cancer Center (MDACC) (Cancer Center Support Grant, CA016672). The Gulf Coast Consortia (GCC) High Throughput Screening Program was supported by CPRIT Grant RP150578. Publisher Copyright: © 2021 The Authors
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
KW - Combination Therapy
KW - CRC
KW - Genomic Biomarker
KW - PDX
UR - http://www.scopus.com/inward/record.url?scp=85108427647&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108427647&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2021.03.022
DO - 10.1053/j.gastro.2021.03.022
M3 - Article
C2 - 33745946
AN - SCOPUS:85108427647
SN - 0016-5085
VL - 161
SP - 196
EP - 210
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -