Mutations in key driver genes of pancreatic cancer: molecularly targeted therapies and other clinical implications

被引:98
作者
Hu, Hai-feng [1 ,2 ,3 ,4 ]
Ye, Zeng [1 ,2 ,3 ,4 ]
Qin, Yi [1 ,2 ,3 ,4 ]
Xu, Xiao-wu [1 ,2 ,3 ,4 ]
Yu, Xian-jun [1 ,2 ,3 ,4 ]
Zhuo, Qi-feng [1 ,2 ,3 ,4 ]
Ji, Shun-rong [1 ,2 ,3 ,4 ]
机构
[1] Fudan Univ, Dept Pancreat Surg, Shanghai Canc Ctr, Shanghai 200032, Peoples R China
[2] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China
[3] Shanghai Pancreat Canc Inst, Shanghai 200032, Peoples R China
[4] Fudan Univ, Pancreat Canc Inst, Shanghai 200032, Peoples R China
基金
中国国家自然科学基金; 美国国家科学基金会;
关键词
pancreatic cancer; KRAS; CDKN2A; TP53; SMAD4; clinical implication; MTOR INHIBITOR EVEROLIMUS; GEMCITABINE PLUS PLACEBO; ORAL MEK INHIBITOR; PHASE-III TRIAL; DUCTAL ADENOCARCINOMA; MUTANT P53; K-RAS; KRAS MUTATIONS; ONCOGENIC KRAS; OPEN-LABEL;
D O I
10.1038/s41401-020-00584-2
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a minimal difference between its incidence rate and mortality rate. Advances in oncology over the past several decades have dramatically improved the overall survival of patients with multiple cancers due to the implementation of new techniques in early diagnosis, therapeutic drugs, and personalized therapy. However, pancreatic cancers remain recalcitrant, with a 5-year relative survival rate of <9%. The lack of measures for early diagnosis, strong resistance to chemotherapy, ineffective adjuvant chemotherapy and the unavailability of molecularly targeted therapy are responsible for the high mortality rate of this notorious disease. Genetically, PDAC progresses as a complex result of the activation of oncogenes and inactivation of tumor suppressors. Although next-generation sequencing has identified numerous new genetic alterations, their clinical implications remain unknown. Classically, oncogenic mutations in genes such as KRAS and loss-of-function mutations in tumor suppressors, such as TP53, CDNK2A, DPC4/SMAD4, and BRCA2, are frequently observed in PDAC. Currently, research on these key driver genes is still the main focus. Therefore, studies assessing the functions of these genes and their potential clinical implications are of paramount importance. In this review, we summarize the biological function of key driver genes and pharmaceutical targets in PDAC. In addition, we conclude the results of molecularly targeted therapies in clinical trials and discuss how to utilize these genetic alterations in further clinical practice.
引用
收藏
页码:1725 / 1741
页数:17
相关论文
共 227 条
[1]   High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients [J].
Allenson, K. ;
Castillo, J. ;
San Lucas, F. A. ;
Scelo, G. ;
Kim, D. U. ;
Bernard, V. ;
Davis, G. ;
Kumar, T. ;
Katz, M. ;
Overman, M. J. ;
Foretova, L. ;
Fabianova, E. ;
Holcatova, I. ;
Janout, V. ;
Meric-Bernstam, F. ;
Gascoyne, P. ;
Wistuba, I. ;
Varadhachary, G. ;
Brennan, P. ;
Hanash, S. ;
Li, D. ;
Maitra, A. ;
Alvarez, H. .
ANNALS OF ONCOLOGY, 2017, 28 (04) :741-747
[2]   MOST HUMAN CARCINOMAS OF THE EXOCRINE PANCREAS CONTAIN MUTANT C-K-RAS GENES [J].
ALMOGUERA, C ;
SHIBATA, D ;
FORRESTER, K ;
MARTIN, J ;
ARNHEIM, N ;
PERUCHO, M .
CELL, 1988, 53 (04) :549-554
[3]  
Antoniou AC, 2014, NEW ENGL J MED, V371, P497, DOI [10.1056/NEJMoa1400382, 10.1056/NEJMc1410673, 10.1056/NEJMc1410673#SA1]
[4]   ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications [J].
Armstrong, Samantha A. ;
Schultz, Christopher W. ;
Azimi-Sadjadi, Ariana ;
Brody, Jonathan R. ;
Pishvaian, Michael J. .
MOLECULAR CANCER THERAPEUTICS, 2019, 18 (11) :1899-1908
[5]   p53 and p16Ink4a/p19Arf Loss Promotes Different Pancreatic Tumor Types from PyMT-Expressing Progenitor Cells [J].
Azzopardi, Stephanie ;
Pang, Sharon ;
Klimstra, David S. ;
Du, Yi-Chieh Nancy .
NEOPLASIA, 2016, 18 (10) :610-617
[6]   Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma [J].
Bachet, J. B. ;
Marechal, R. ;
Demetter, P. ;
Bonnetain, F. ;
Couvelard, A. ;
Svrcek, M. ;
Bardier-Dupas, A. ;
Hammel, P. ;
Sauvanet, A. ;
Louvet, C. ;
Paye, F. ;
Rougier, P. ;
Penna, C. ;
Vaillant, J. C. ;
Andre, T. ;
Closset, J. ;
Salmon, I. ;
Emile, J. F. ;
Van Laethem, J. L. .
ANNALS OF ONCOLOGY, 2012, 23 (09) :2327-2335
[7]   Genomic analyses identify molecular subtypes of pancreatic cancer [J].
Bailey, Peter ;
Chang, David K. ;
Nones, Katia ;
Johns, Amber L. ;
Patch, Ann-Marie ;
Gingras, Marie-Claude ;
Miller, David K. ;
Christ, Angelika N. ;
Bruxner, Tim J. C. ;
Quinn, Michael C. ;
Nourse, Craig ;
Murtaugh, L. Charles ;
Harliwong, Ivon ;
Idrisoglu, Senel ;
Manning, Suzanne ;
Nourbakhsh, Ehsan ;
Wani, Shivangi ;
Fink, Lynn ;
Holmes, Oliver ;
Chin, Vencssa ;
Anderson, Matthew J. ;
Kazakoff, Stephen ;
Leonard, Conrad ;
Newell, Felicity ;
Waddell, Nick ;
Wood, Scott ;
Xu, Qinying ;
Wilson, Peter J. ;
Cloonan, Nicole ;
Kassahn, Karin S. ;
Taylor, Darrin ;
Quek, Kelly ;
Robertson, Alan ;
Pantano, Lorena ;
Mincarelli, Laura ;
Sanchez, Luis N. ;
Evers, Lisa ;
Wu, Jianmin ;
Pinese, Mark ;
Cowley, Mark J. ;
Jones, Marc D. ;
Colvin, Emily K. ;
Nagrial, Adnan M. ;
Humphrey, Emily S. ;
Chantrill, Lorraine A. ;
Mawson, Amanda ;
Humphris, Jeremy ;
Chou, Angela ;
Pajic, Marina ;
Scarlett, Christopher J. .
NATURE, 2016, 531 (7592) :47-+
[8]   Modeling Pancreatic Cancer with Organoids [J].
Baker, Lindsey A. ;
Tiriac, Herve ;
Clevers, Hans ;
Tuveson, David A. .
TRENDS IN CANCER, 2016, 2 (04) :176-190
[9]   Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse [J].
Bardeesy, N ;
Aguirre, AJ ;
Chu, GC ;
Cheng, KH ;
Lopez, LV ;
Hezel, AF ;
Feng, B ;
Brennan, C ;
Weissleder, R ;
Mahmood, U ;
Hanahan, D ;
Redston, MS ;
Chin, L ;
DePinho, RA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) :5947-5952
[10]   Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer [J].
Bardeesy, Nabeel ;
Cheng, Kuang-hung ;
Berger, Justin H. ;
Chu, Gerald C. ;
Pahler, Jessica ;
Olson, Peter ;
Hezel, Aram F. ;
Horner, James ;
Lauwers, Gregory Y. ;
Hanahan, Douglas ;
DePinho, Ronald A. .
GENES & DEVELOPMENT, 2006, 20 (22) :3130-3146