Review
Cell Biology
Zining Zhang, Heng Zhang, Xiang Liao, Hsiang-i Tsai
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a common and aggressive type of pancreatic cancer with a poor survival rate. The highest mutation frequency in PDAC is observed in the KRAS gene, which plays a critical role in promoting cancer cell growth, resistance to therapy, and poor prognosis. This review focuses on the patterns of KRAS mutations in PDAC and highlights its role in signal transduction, metabolic reprogramming, therapy resistance, and prognosis, aiming to provide potential KRAS-targeted therapies for PDAC.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Medicine, Research & Experimental
Yiran Zhou, Jiabin Jin, Yuchen Ji, Jiaqiang Zhang, Ningzhen Fu, Mengmin Chen, Jun Wang, Kai Qin, Yu Jiang, Dongfeng Cheng, Xiaxing Deng, Baiyong Shen
Summary: This study revealed the impact of different TP53 mutation subtypes on the clinical characteristics and outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). TP53 missense mutation was associated with poor tumor differentiation and revealed gain-of-function properties in small-sized KRAS transformed PDAC. It was also found that TP53 missense mutation was associated with reduced disease-free survival and overall survival in patients who did not receive chemotherapy, but higher overall survival in patients who received chemotherapy.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Cell Biology
Pingping Hou, Xingdi Ma, Zecheng Yang, Qiang Zhang, Chang-Jiun Wu, Jun Li, Lin Tan, Wantong Yao, Liang Yan, Xin Zhou, Alec C. Kimmelman, Philip L. Lorenzi, Jianhua Zhang, Shan Jiang, Denise Spring, Y. Alan Wang, Ronald A. DePinho
Summary: The study uncovers USP21 as a driver of KRAS*-independent PDAC growth by inducing macropinocytosis, which maintains intracellular amino acid levels. USP21 may play a role in affecting responsiveness to emergent anti-KRAS* therapy.
GENES & DEVELOPMENT
(2021)
Article
Multidisciplinary Sciences
Derek K. Cheng, Tobiloba E. Oni, Jennifer S. Thalappillil, Youngkyu Park, Hsiu-Chi Ting, Brinda Alagesan, Nadia V. Prasad, Kenneth Addison, Keith D. Rivera, Darryl J. Pappin, Linda Van Aelst, David A. Tuveson
Summary: The study identified protein interactors of active KRAS in PDAC cells using proximity labeling, revealing that RSK1 selectively interacts with membrane-bound KRASG12D through NF1 and SPRED2. It was found that membrane RSK1 mediates negative feedback on WT RAS signaling and impedes the proliferation of pancreatic cancer cells upon the ablation of mutant KRAS in PDAC, highlighting the role of WT RAS signaling in promoting adaptive resistance to mutant KRAS-specific inhibitors.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Gastroenterology & Hepatology
Leiling Pan, Medhanie A. Mulaw, Johann Gout, Min Guo, Hina Zarrin, Peggy Schwarz, Bernd Baumann, Thomas Seufferlein, Martin Wagner, Franz Oswald
Summary: This study found that downregulation of RBPJ in PDAC patients promotes KRAS-mediated transformation of pancreatic acinar cells and development of fibrosis. This finding provides important clues for the development mechanism of PDAC and offers a theoretical basis for finding new treatment strategies.
CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
(2023)
Article
Oncology
Keita Hanada, Kenji Kawada, Gen Nishikawa, Kosuke Toda, Hisatsugu Maekawa, Yasuyo Nishikawa, Hideyuki Masui, Wataru Hirata, Michio Okamoto, Yoshiyuki Kiyasu, Shusaku Honma, Ryotaro Ogawa, Rei Mizuno, Yoshiro Itatani, Hiroyuki Miyoshi, Takehiko Sasazuki, Senji Shirasawa, M. Mark Taketo, Kazutaka Obama, Yoshiharu Sakai
Summary: Mutations in the KRAS gene are commonly found in various cancers, including colorectal cancer. Studies have shown that KRAS-mutant CRC cells enhance macropinocytosis for tumor growth under nutrient-depleted conditions, and this process is closely correlated with asparagine metabolism. Inhibition of both macropinocytosis and asparagine availability could be a promising therapeutic strategy for KRAS-mutant cancers.
Article
Oncology
Sami-Alexander Safi, Lena Haeberle, Wolfgang Goering, Verena Keitel, Georg Fluegen, Nikolas Stoecklein, Alexander Rehders, Wolfram Trudo Knoefel, Irene Esposito
Summary: Long-term survivors of pancreatic cancer have a distinct molecular profile compared to other patients, which can contribute to improved stratification and management of pancreatic cancer patients. However, larger studies are needed to confirm these findings and potentially identify rare potential targets for targeted therapy in pancreatic cancer.
Editorial Material
Cell Biology
Hua Su, Fei Yang, Beicheng Sun, Michael Karin
Summary: Inhibition of autophagy leads to upregulation of macropinocytosis (MP) in cancer cells, allowing them to overcome autophagy deficiency and sustain their bioenergetic demands. The NFE2L2/NRF2-driven induction of MP-related genes (MRGs) is responsible for the upregulation of MP in autophagy-inhibited, hypoxic, and oxidative-stress-exposed cancer cells. Simultaneous blockade of autophagy and MP effectively cuts off nutrient and supplies to cancer cells, leading to rapid tumor regression.
Review
Oncology
Joshua Zhang, Lily Darman, Md Sazzad Hassan, Urs Von Holzen, Niranjan Awasthi
Summary: KRAS is a frequently mutated oncogene in solid tumors and plays an important role in PDAC. However, targeting KRAS has been challenging due to its unique properties. Recent research has focused on inhibiting the activation of downstream signaling pathways, but practical limitations still exist in clinical applications.
Review
Oncology
Victor Hugo Fonseca de Jesus, Maria Cecilia Mathias-Machado, Joao Paulo Fogacci de Farias, Marcelo Porfirio Sunagua Aruquipa, Alexandre A. Jacome, Renata D'Alpino Peixoto
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with poor prognosis. The discovery of KRAS mutations as a pivotal event in pancreatic carcinogenesis has opened new avenues for targeted therapy. Recent research has provided insights into the different KRAS mutations, their prognostic implications, and therapeutic opportunities. Inhibitors of KRAS signaling, particularly KRAS G12C inhibitors, have shown promise in clinical trials. Overall, understanding the role of KRAS in PDAC offers hope for a significant improvement in treatment outcomes.
Article
Biochemistry & Molecular Biology
Rodrigo Entrialgo-Cadierno, Cristina Cueto-Urena, Connor Welch, Iker Feliu, Irati Macaya, Laura Vera, Xabier Morales, Sandra Vietti Michelina, Pietro Scaparone, Ines Lopez, Elodie Darbo, Oihane Erice, Adrian Vallejo, Haritz Moreno, Ainhoa Goni-Salaverri, David Lara-Astiaso, Nils Halberg, Ivan Cortes-Dominguez, Elizabeth Guruceaga, Chiara Ambrogio, Fernando Lecanda, Silve Vicent
Summary: PITPNC1 is a functionally relevant KRAS effector in LUAD and PDAC, associated with tumor growth and metastasis.
Article
Oncology
Dasom Kim, Dongwha Min, Joohee Kim, Min Jung Kim, Yerim Seo, Byung Hwa Jung, Seung-Hae Kwon, Hyunju Ro, Seoee Lee, Jason K. Sa, Ji-Yun Lee
Summary: In this study, nutlin-3a, an MDM2 antagonist, was found to inhibit the KRAS-PI3K/Akt-mTOR pathway and disrupt the fusion of autophagosomes and macropinosomes with lysosomes. This led to a non-apoptotic and catastrophic macropinocytosis-like cell death, which was dependent on GFPT2 of the hexosamine biosynthetic pathway in KRAS mutant/p53 wild type NSCLC cells.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2023)
Review
Medicine, Research & Experimental
Huiqin Liu, Feng Qian
Summary: KRAS mutations are common in cancer, especially in pancreatic, lung, and colorectal cancers. Macropinocytosis, a metabolic feature in KRAS-driven tumors, can be exploited for selective drug delivery into KRAS mutant cancer cells. This article summarizes studies on KRAS mutation-induced macropinocytosis, reviews recent advances in macropinocytosis enhancement for drug delivery to KRAS mutant cancer cells, and discusses the potential opportunities and challenges of this strategy.
Article
Oncology
Nayela N. Chowdhury, Yi Yang, Ananya Dutta, Michelle Luo, Zimu Wei, Sara R. Abrahams, Alexey S. Revenko, Fenil Shah, Lindsey A. Miles, Robert J. Parmer, Bas de Laat, Alisa S. Wolberg, James P. Luyendyk, Melissa L. Fishel, Matthew J. Flick
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal metastatic disease associated with robust activation of the coagulation and fibrinolytic systems. Primary fibrinolytic protease plasminogen promotes PDAC tumor growth and metastatic potential through engaging plasminogen receptors on tumor cells.
MOLECULAR ONCOLOGY
(2024)
Review
Oncology
Yongde Luo, Xiaokun Li, Jianjia Ma, James L. Abbruzzese, Weiqin Lu
Summary: Mutant KRAS is a key driver of pancreatic cancer, but its activity is regulated by upstream stimuli. Obesity exacerbates mutant KRAS-mediated pathologies, but the mechanistic link between obesity and pancreatic cancer remains unclear.
Review
Biochemistry & Molecular Biology
Silvia Arcucci, Fernanda Ramos-Delgado, Coralie Cayron, Nicole Therville, Marie-Pierre Gratacap, Celine Basset, Benoit Thibault, Julie Guillermet-Guibert
Summary: PI3Ks are important lipid kinases that produce phosphoinositides, with three classes including PI3Kα and PI3Kβ in vertebrates. These isoforms share similar protein domains and lipid substrate specificity. In addition to redundancy, PI3Kα and PI3Kβ cooperate in integrating specific signals for organ development, physiology, and disease.
BIOCHEMICAL JOURNAL
(2021)
Article
Medicine, Research & Experimental
Benoit Thibault, Fernanda Ramos-Delgado, Elvire Pons-Tostivint, Nicole Therville, Celia Cintas, Silvia Arcucci, Stephanie Cassant-Sourdy, Gabriela Reyes-Castellanos, Marie Tosolini, Amelie V. Villard, Coralie Cayron, Romain Baer, Justine Bertrand-Michel, Delphine Pagan, Dina Ferreira Da Mota, Hongkai Yan, Chiara Falcomata, Fabrice Muscari, Barbara Bournet, Jean-Pierre Delord, Ezra Aksoy, Alice Carrier, Pierre Cordelier, Dieter Saur, Celine Basset, Julie Guillermet-Guibert
Summary: Studies have shown that the PI3K pathway and PI3Kα activation signature can predict the aggressiveness and prognosis of PDAC. Pharmacological inhibition of PI3Kα can delay tumor cell migratory behavior, preventing macro-metastatic evolution.
EMBO MOLECULAR MEDICINE
(2021)
Article
Oncology
Celia Cintas, Thibault Douche, Zahra Dantes, Emmanuelle Mouton-Barbosa, Marie-Pierre Bousquet, Coralie Cayron, Nicole Therville, Frederic Pont, Fernanda Ramos-Delgado, Camille Guyon, Barbara Garmy-Susini, Paola Cappello, Odile Burlet-Schiltz, Emilio Hirsch, Anne Gomez-Brouchet, Benoit Thibault, Maximilian Reichert, Julie Guillermet-Guibert
Summary: The PI3K pathway is highly active in human cancers and its inhibition is a potential therapeutic strategy for pancreatic cancer. However, different isoform-selective PI3K inhibitors have varying effects, with some leading to reactivation of downstream signaling. Combining inhibitors with different isoform selectivity may prevent the induction of compensatory signals and have a synergistic effect on cell survival.
MOLECULAR CANCER THERAPEUTICS
(2021)
Editorial Material
Gastroenterology & Hepatology
C. Cayron, S. Rigal, J. Guillermet-Guibert
Summary: Pancreatic ductal adenocarcinoma is characterized by low immunogenicity and high autophagy flux, contributing to tumor progression. Understanding and targeting these mechanisms are crucial for improving treatment outcomes and patient survival.
CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY
(2021)
Review
Gastroenterology & Hepatology
Leonard Depotte, Juliette Palle, Cosimo Rasola, Chloe Broudin, Vlad-Adrian Afrasanie, Antoine Mariani, Aziz Zaanan
Summary: Advanced gastric adenocarcinoma is a disease with poor prognosis. In recent years, new drugs, such as trastuzumab for HER2-positive tumors, ramucirumab alone or in combination with paclitaxel, and trifluridine-tipiracil, have improved patient survival. Other drugs, including monoclonal antibodies and targeted therapies, are also being evaluated.
CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY
(2024)
