American Association for Cancer Research
21598290cd140362-sup-fig6.pdf (238.6 kB)

Supplementary Figure 6 from Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations

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journal contribution
posted on 2023-04-03, 20:40 authored by Annan Yang, N.V. Rajeshkumar, Xiaoxu Wang, Shinichi Yabuuchi, Brian M. Alexander, Gerald C. Chu, Daniel D. Von Hoff, Anirban Maitra, Alec C. Kimmelman

PDF file - 239KB, Western blot showed inhibition of autophagy in Atg5 and Atg7 knockdown cell lines.



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 patient-derived 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. Cancer Discov; 4(8); 905–13. ©2014 AACR.See related commentary by Amaravadi and Debnath, p. 873This article is highlighted in the In This Issue feature, p. 855