Abstract:
UNLABELLED: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.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Yang A,Rajeshkumar NV,Wang X,Yabuuchi S,Alexander BM,Chu GC,Von Hoff DD,Maitra A,Kimmelman ACdoi
10.1158/2159-8290.CD-14-0362subject
Has Abstractpub_date
2014-08-01 00:00:00pages
905-13issue
8eissn
2159-8274issn
2159-8290pii
2159-8290.CD-14-0362journal_volume
4pub_type
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