Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations

Annan Yang, N. V. Rajeshkumar, Xiaoxu Wang, Shinichi Yabuuchi, Brian M. Alexander, Gerald C. Chu, Daniel D. Von Hoff, Anirban Maitra, Alec C. Kimmelman

Research output: Contribution to journalArticle

Abstract

Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patientderived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status. SIGNIFICANCE: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials.

Original languageEnglish (US)
Pages (from-to)905-913
Number of pages9
JournalCancer Discovery
Volume4
Issue number8
DOIs
StatePublished - 2014

Fingerprint

Autophagy
Growth
Neoplasms
Pancreatic Neoplasms
Heterografts
Hydroxychloroquine
Tumor Cell Line
Pancreas
Adenocarcinoma
Clinical Trials
Cell Line
Survival
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

Yang, A., Rajeshkumar, N. V., Wang, X., Yabuuchi, S., Alexander, B. M., Chu, G. C., ... Kimmelman, A. C. (2014). Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discovery, 4(8), 905-913. https://doi.org/10.1158/2159-8290.CD-14-0362

Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. / Yang, Annan; Rajeshkumar, N. V.; Wang, Xiaoxu; Yabuuchi, Shinichi; Alexander, Brian M.; Chu, Gerald C.; Von Hoff, Daniel D.; Maitra, Anirban; Kimmelman, Alec C.

In: Cancer Discovery, Vol. 4, No. 8, 2014, p. 905-913.

Research output: Contribution to journalArticle

Yang, A, Rajeshkumar, NV, Wang, X, Yabuuchi, S, Alexander, BM, Chu, GC, Von Hoff, DD, Maitra, A & Kimmelman, AC 2014, 'Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations', Cancer Discovery, vol. 4, no. 8, pp. 905-913. https://doi.org/10.1158/2159-8290.CD-14-0362
Yang, Annan ; Rajeshkumar, N. V. ; Wang, Xiaoxu ; Yabuuchi, Shinichi ; Alexander, Brian M. ; Chu, Gerald C. ; Von Hoff, Daniel D. ; Maitra, Anirban ; Kimmelman, Alec C. / Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. In: Cancer Discovery. 2014 ; Vol. 4, No. 8. pp. 905-913.
@article{96baefb2e06247cea47219f5d0a6ce02,
title = "Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations",
abstract = "Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patientderived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status. SIGNIFICANCE: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials.",
author = "Annan Yang and Rajeshkumar, {N. V.} and Xiaoxu Wang and Shinichi Yabuuchi and Alexander, {Brian M.} and Chu, {Gerald C.} and {Von Hoff}, {Daniel D.} and Anirban Maitra and Kimmelman, {Alec C.}",
year = "2014",
doi = "10.1158/2159-8290.CD-14-0362",
language = "English (US)",
volume = "4",
pages = "905--913",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations

AU - Yang, Annan

AU - Rajeshkumar, N. V.

AU - Wang, Xiaoxu

AU - Yabuuchi, Shinichi

AU - Alexander, Brian M.

AU - Chu, Gerald C.

AU - Von Hoff, Daniel D.

AU - Maitra, Anirban

AU - Kimmelman, Alec C.

PY - 2014

Y1 - 2014

N2 - Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patientderived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status. SIGNIFICANCE: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials.

AB - Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patientderived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status. SIGNIFICANCE: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials.

UR - http://www.scopus.com/inward/record.url?scp=84905499163&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905499163&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-14-0362

DO - 10.1158/2159-8290.CD-14-0362

M3 - Article

C2 - 24875860

AN - SCOPUS:84905499163

VL - 4

SP - 905

EP - 913

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 8

ER -