The
n e w e ng l a n d j o u r na l
of
m e dic i n e
clinical implications of basic research Elizabeth G. Phimister, Ph.D., Editor
Autophagy, p53, and Pancreatic Cancer Christine A. Iacobuzio-Donahue, M.D., Ph.D., and Joseph M. Herman, M.D. In this age of environmental awareness and be- volves the formation of intracellular vesicles, ing green, one can take a lesson from eukaryotic called autophagosomes, which deliver long-lived cells. An efficient process called autophagy in- proteins and excess organelles to lysosomes for Normal
Low-Grade Pancreatic Intraepithelial Neoplasia
High-Grade Pancreatic Intraepithelial Neoplasia
Pancreatic Ductal Adenocarcinoma
Duct lumen
Duct epithelial cells
Connective tissue
KRAS-activating -activating mutation (in >95% of patients)
TP53-inactivating mutation (in >75% of patients)
Suppresses tumor progression
Hydroxychloroquine (autophagy inhibitor)
Enhances tumor progression
Hydroxychloroquine (autophagy inhibitor)
Figure 1. Genetics of Pancreatic Carcinogenesis. The development of KRAS mutations in normal epithelial cells, which is found in more than 95% of patients with pancreatic carcinoma, leads to the formation of low-grade pancreatic intraepithelial neoplastic lesions. Over time, the accumulation of additional mutations, COLOR FIGURE such as in the gene encoding the tumor-suppressor protein p53 (TP53), which are found in more than 75% of patients Draft 8 with tumors, 3/17/14 leads to the development of high-grade pancreatic intraepithelial neoplastic lesions and pancreatic cancer. In Author a recent study, Rosenfeldt Iacobuzio-Donahue 1 the progression of # et al.2 used a transgenic model of pancreatic ductal adenocarcinoma to show that the inhibition of autophagyFig blocks Autophagy, p53, and Titleand low-grade pancreatic intraepithelial neoplastic lesions to high-grade pancreatic intraepithelial neoplastic lesions cancercancer in mice with pancreatic wild-type Trp53, whereas the inhibition of autophagy in the presence of Trp53 mutations promotes cancer formation. These findings ME suggest that the characterization of TP53 status will help to identify patients with newly diagnosed pancreatic DE ductalPhimister adenocarcinoma Artist N Koscal who may benefit the most from autophagy inhibitors. AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully
Issue date
1352
n engl j med 370;14
nejm.org
4/3/14
april 3, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
clinical implications of basic research
degradation. The macromolecule products of this degradation are then used in a variety of cellular processes.1 Not surprisingly, the dysregulation of autophagy plays a major role in several human diseases, including cancer. However, whether autophagy promotes or suppresses neoplasia has been a topic of debate. Recent evidence reported by Rosenfeldt et al.2 clarifies the role of autophagy in a well-described mouse model of pancreatic ductal adenocarcinoma and its intimate link to the mutational status of Trp53, the mouse gene encoding the homologue of human tumor-suppressor protein p53. In the mouse model of pancreatic ductal adeno carcinoma used by Rosenfeldt et al., the oncogene Kras is turned on in the epithelial compartment of the pancreas. The authors found that the conditional inactivation of Atg7, a key mediator of autophagy, blocked mutant Kras–induced progression to invasive pancreatic ductal adenocarcinoma. This blockade was due to an enhancement of cell death, growth arrest, and senescence of early-stage pancreatic intraepithelial neoplastic lesions. By contrast, the conditional inactivation of Atg7 in the context of coexistent mutant Kras and Trp53 deletion not only failed to block progression to invasive pancreatic ductal adenocarcinoma but also enhanced it. The pharmacologic inhibition of autophagy by hydroxychloroquine in these mice produced the same effects as Atg7 deletion, indicating that the tumor-suppressive versus tumor-promoting aspects of autophagy may be related to the functional status of Trp53. The findings of Rosenfeldt et al. have three immediate clinical implications. First, given that KRAS activation is an early event in human pancreatic carcinogenesis, whereas TP53 inactivation is a late event,3 the inhibition of autophagy may prevent the development of pancreatic ductal adenocarcinoma (Fig. 1). This approach may be particularly relevant for patients at increased risk for this disease.4 Second, the treatment of patients with pancreatic cancer who are receiving pharmacologic inhibitors of autophagy, such as hydroxychloroquine, in the context of coexistent KRAS and TP53 mutations may actually spur tumor progression. Approximately 75% of pancreatic ductal adenocarcinomas have coexistent KRAS and TP53 alterations,5 and there are currently five active clinical trials evaluating the role of hydroxychloroquine in patients with resectable and advanced
pancreatic cancer (ClinicalTrials.gov numbers, NCT01494155, NCT01978184, NCT01506973, NCT01128296, and NCT01273805). Conversely, selected patients with intact TP53 status may benefit from autophagy inhibitors as a component of their adjuvant or first-line treatment. The genetic characterization of pancreatic ductal adenocarcinomas before treatment may allow for better selection of specific therapeutic regimens, and aggressive, combined treatment methods with the use of autophagy inhibitors in these selected patients may provide an opportunity for cure. Third, these findings may explain controversial data suggesting that increased PET-avidity, a functional measure of metabolism assessed by means of positron-emission tomography (PET), correlates with inferior survival among patients with locally advanced pancreatic cancer. For example, Rosenfeldt et al. found that in adenocarcinomas with intact Trp53, the loss of autophagy resulted in decreased oxygen consumption and metabolism, whereas in adenocarcinomas that did not have Trp53, the loss of autophagy caused an increase in glucose consumption. This finding suggests that there may be a genetic or molecular basis to variations in PET-avidity. An improved understanding of the interplay of genetics, autophagy, tumor metabolism, and PET-avidity or other functional imaging may allow for the noninvasive selection of patients with carcinomas with nonmutated TP53, who are more likely to benefit from autophagy inhibitors than are patients with tumors with mutated forms of TP53. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Department of Pathology and the David Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan-Kettering Cancer Center, New York (C.A.I.-D.); and the Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore (J.M.H.). 1. Mizushima N, Komatsu M. Autophagy: renovation of cells
and tissues. Cell 2011;147:728-41.
2. Rosenfeldt MT, O’Prey J, Morton JP, et al. p53 Status deter-
mines the role of autophagy in pancreatic tumour development. Nature 2013;504:296-300. 3. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:2969-72. 4. Klein AP, Lindström S, Mendelsohn JB, et al. An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS One 2013;8(9):e72311. 5. Yachida S, White CM, Naito Y, et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res 2012;18:6339-47. DOI: 10.1056/NEJMcibr1400189 Copyright © 2014 Massachusetts Medical Society.
n engl j med 370;14 nejm.org april 3, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1353
n e w e ng l a n d j o u r na l
of
m e dic i n e
clinical implications of basic research Elizabeth G. Phimister, Ph.D., Editor
Autophagy, p53, and Pancreatic Cancer Christine A. Iacobuzio-Donahue, M.D., Ph.D., and Joseph M. Herman, M.D. In this age of environmental awareness and be- volves the formation of intracellular vesicles, ing green, one can take a lesson from eukaryotic called autophagosomes, which deliver long-lived cells. An efficient process called autophagy in- proteins and excess organelles to lysosomes for Normal
Low-Grade Pancreatic Intraepithelial Neoplasia
High-Grade Pancreatic Intraepithelial Neoplasia
Pancreatic Ductal Adenocarcinoma
Duct lumen
Duct epithelial cells
Connective tissue
KRAS-activating -activating mutation (in >95% of patients)
TP53-inactivating mutation (in >75% of patients)
Suppresses tumor progression
Hydroxychloroquine (autophagy inhibitor)
Enhances tumor progression
Hydroxychloroquine (autophagy inhibitor)
Figure 1. Genetics of Pancreatic Carcinogenesis. The development of KRAS mutations in normal epithelial cells, which is found in more than 95% of patients with pancreatic carcinoma, leads to the formation of low-grade pancreatic intraepithelial neoplastic lesions. Over time, the accumulation of additional mutations, COLOR FIGURE such as in the gene encoding the tumor-suppressor protein p53 (TP53), which are found in more than 75% of patients Draft 8 with tumors, 3/17/14 leads to the development of high-grade pancreatic intraepithelial neoplastic lesions and pancreatic cancer. In Author a recent study, Rosenfeldt Iacobuzio-Donahue 1 the progression of # et al.2 used a transgenic model of pancreatic ductal adenocarcinoma to show that the inhibition of autophagyFig blocks Autophagy, p53, and Titleand low-grade pancreatic intraepithelial neoplastic lesions to high-grade pancreatic intraepithelial neoplastic lesions cancercancer in mice with pancreatic wild-type Trp53, whereas the inhibition of autophagy in the presence of Trp53 mutations promotes cancer formation. These findings ME suggest that the characterization of TP53 status will help to identify patients with newly diagnosed pancreatic DE ductalPhimister adenocarcinoma Artist N Koscal who may benefit the most from autophagy inhibitors. AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset Please check carefully
Issue date
1352
n engl j med 370;14
nejm.org
4/3/14
april 3, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
clinical implications of basic research
degradation. The macromolecule products of this degradation are then used in a variety of cellular processes.1 Not surprisingly, the dysregulation of autophagy plays a major role in several human diseases, including cancer. However, whether autophagy promotes or suppresses neoplasia has been a topic of debate. Recent evidence reported by Rosenfeldt et al.2 clarifies the role of autophagy in a well-described mouse model of pancreatic ductal adenocarcinoma and its intimate link to the mutational status of Trp53, the mouse gene encoding the homologue of human tumor-suppressor protein p53. In the mouse model of pancreatic ductal adeno carcinoma used by Rosenfeldt et al., the oncogene Kras is turned on in the epithelial compartment of the pancreas. The authors found that the conditional inactivation of Atg7, a key mediator of autophagy, blocked mutant Kras–induced progression to invasive pancreatic ductal adenocarcinoma. This blockade was due to an enhancement of cell death, growth arrest, and senescence of early-stage pancreatic intraepithelial neoplastic lesions. By contrast, the conditional inactivation of Atg7 in the context of coexistent mutant Kras and Trp53 deletion not only failed to block progression to invasive pancreatic ductal adenocarcinoma but also enhanced it. The pharmacologic inhibition of autophagy by hydroxychloroquine in these mice produced the same effects as Atg7 deletion, indicating that the tumor-suppressive versus tumor-promoting aspects of autophagy may be related to the functional status of Trp53. The findings of Rosenfeldt et al. have three immediate clinical implications. First, given that KRAS activation is an early event in human pancreatic carcinogenesis, whereas TP53 inactivation is a late event,3 the inhibition of autophagy may prevent the development of pancreatic ductal adenocarcinoma (Fig. 1). This approach may be particularly relevant for patients at increased risk for this disease.4 Second, the treatment of patients with pancreatic cancer who are receiving pharmacologic inhibitors of autophagy, such as hydroxychloroquine, in the context of coexistent KRAS and TP53 mutations may actually spur tumor progression. Approximately 75% of pancreatic ductal adenocarcinomas have coexistent KRAS and TP53 alterations,5 and there are currently five active clinical trials evaluating the role of hydroxychloroquine in patients with resectable and advanced
pancreatic cancer (ClinicalTrials.gov numbers, NCT01494155, NCT01978184, NCT01506973, NCT01128296, and NCT01273805). Conversely, selected patients with intact TP53 status may benefit from autophagy inhibitors as a component of their adjuvant or first-line treatment. The genetic characterization of pancreatic ductal adenocarcinomas before treatment may allow for better selection of specific therapeutic regimens, and aggressive, combined treatment methods with the use of autophagy inhibitors in these selected patients may provide an opportunity for cure. Third, these findings may explain controversial data suggesting that increased PET-avidity, a functional measure of metabolism assessed by means of positron-emission tomography (PET), correlates with inferior survival among patients with locally advanced pancreatic cancer. For example, Rosenfeldt et al. found that in adenocarcinomas with intact Trp53, the loss of autophagy resulted in decreased oxygen consumption and metabolism, whereas in adenocarcinomas that did not have Trp53, the loss of autophagy caused an increase in glucose consumption. This finding suggests that there may be a genetic or molecular basis to variations in PET-avidity. An improved understanding of the interplay of genetics, autophagy, tumor metabolism, and PET-avidity or other functional imaging may allow for the noninvasive selection of patients with carcinomas with nonmutated TP53, who are more likely to benefit from autophagy inhibitors than are patients with tumors with mutated forms of TP53. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Department of Pathology and the David Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan-Kettering Cancer Center, New York (C.A.I.-D.); and the Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Hospital, Baltimore (J.M.H.). 1. Mizushima N, Komatsu M. Autophagy: renovation of cells
and tissues. Cell 2011;147:728-41.
2. Rosenfeldt MT, O’Prey J, Morton JP, et al. p53 Status deter-
mines the role of autophagy in pancreatic tumour development. Nature 2013;504:296-300. 3. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000;6:2969-72. 4. Klein AP, Lindström S, Mendelsohn JB, et al. An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS One 2013;8(9):e72311. 5. Yachida S, White CM, Naito Y, et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin Cancer Res 2012;18:6339-47. DOI: 10.1056/NEJMcibr1400189 Copyright © 2014 Massachusetts Medical Society.
n engl j med 370;14 nejm.org april 3, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on April 9, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1353
