Article
Multidisciplinary Sciences
Nicholas H. Juul, Jung-Ki Yoon, Marina C. Martinez, Neha Rishi, Yana I. Kazadaeva, Maurizio Morri, Norma F. Neff, Winston L. Trope, Joseph B. Shrager, Rahul Sinha, Tushar J. Desai
Summary: This study identifies a new cell of origin for lung adenocarcinoma, the AT1 cell, which can be reprogrammed into AT2 stem cells after expressing KRAS(G12D) and subsequently form indolent tumors. These tumor cells spread slowly along alveolar walls in a non-destructive manner and have low ERK activity, resembling human lepidic adenocarcinoma.
Review
Oncology
Sahar F. Bannoura, Husain Yar Khan, Asfar S. Azmi
Summary: KRAS mutations are common in cancer, and recent advancements have shown that small molecule inhibitors can be developed against KRAS G12C, although there is still no agent to target KRAS G12D. However, significant progress has been made in developing compounds that can bind to and inhibit KRAS G12D, including MRTX1133. Additionally, an immunotherapeutic approach using adoptive T-cell transfer has shown promise in targeting G12D in pancreatic cancer.
FRONTIERS IN ONCOLOGY
(2022)
Article
Oncology
Samantha B. Kemp, Noah Cheng, Nune Markosyan, Rina Sor, Il-Kyu Kim, Jill Hallin, Jason Shoush, Liz Quinones, Natalie V. Brown, Jared B. Bassett, Nikhil Joshi, Salina Yuan, Molly Smith, William P. Vostrejs, Kia Z. Perez-Vale, Benjamin Kahn, Feiyan Mo, Timothy R. Donahue, Caius G. Radu, Cynthia Clendenin, James G. Christensen, Robert H. Vanderheide, Ben Z. Stanger
Summary: This study evaluated the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in PDAC models with an intact immune system. The results showed that MRTX1133 can induce deep tumor regressions and alter the tumor microenvironment, demonstrating its potential as a novel therapy for PDAC patients. Further clinical testing is warranted.
Article
Cell Biology
Henry Shen, Joanne Lundy, Andrew H. Strickland, Marion Harris, Michael Swan, Christopher Desmond, Brendan J. Jenkins, Daniel Croagh
Summary: This study found that the detection of KRAS G12D mutation subtype in pancreatic ductal adenocarcinoma (PDAC) patients is not a determinant of poorer prognosis and survival. However, among resectable KRAS G12D patients, their survival was significantly shorter compared to other genotypes.
Article
Biochemistry & Molecular Biology
Yu Ma, Sunkai Ling, Yuan Li, Mingyue Hu, Bo Kong, Peilin Huang, Hui Liu
Summary: This study investigates the regulatory link between hypoxia-inducible factor-2 alpha (HIF-2 alpha) and glutamine metabolism in pancreatic ductal adenocarcinoma (PDAC) cells with KRAS loss of heterozygosity (LOH). The results demonstrate that KRAS LOH stimulates HIF-2 alpha activity, which activates c-Myc and leads to nonclassical glutamine metabolism. Targeting HIF-2 alpha-c-Myc regulated glutamine metabolism may provide a new therapeutic approach for KRAS LOH PDAC.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
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
Oncology
Yao Kong, Yuming Luo, Shangyou Zheng, Jiabin Yang, Dingwen Zhang, Yue Zhao, Hanhao Zheng, Mingjie An, Yan Lin, Le Ai, Xiayao Diao, Qing Lin, Changhao Chen, Rufu Chen
Summary: This study identified a novel circRNA, circARFGEF2, which is upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) and positively associated with lymph node metastasis. The biogenesis of circARFGEF2 is activated by the alternative splicing factor QKI-5 and it promotes metastasis by sponging miR-1205 and activating JAK2.
Review
Biochemistry & Molecular Biology
Enrico Gurreri, Giannicola Genovese, Luigi Perelli, Antonio Agostini, Geny Piro, Carmine Carbone, Giampaolo Tortora
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with increasing incidence and poor survival rate. More than 90% of PDAC patients have KRAS mutations, which are difficult to target directly. KRAS regulates key downstream pathways and induces acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) in a KRAS-dependent manner. KRAS dependency in PDAC is crucial, and cancer cells have developed compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors. This review provides insights into KRAS dependency in PDAC and the development of compensatory escape mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Medicine, General & Internal
Elena De Falco, Luca Pacini, Daniela Bastianelli, Gian Paolo Spinelli, Chiara Spoto, Enzo Veltri, Antonella Calogero
Summary: Colorectal cancer (CRC) is on the rise, ranking as the second most common cause of cancer-related deaths. The management of CRC is focused on mutations in the RAS family protein, particularly single mutations in KRAS which are both characteristic and targetable. Double mutations in KRAS cannot be interpreted as straightforward genomic alterations and may have a significant impact on the clinical outcome of CRC patients, necessitating closer monitoring.
Article
Multidisciplinary Sciences
Wuguo Li, Wei Chen, Jialin Wang, Guangyin Zhao, Lianzhou Chen, Yong Wan, Qianxin Luo, Wenwen Li, Haoji Huang, Wenying Li, Wu Li, Yutong Yang, Daici Chen, Qiao Su
Summary: The combination of PDX models with CD-DST assay is a comprehensive and feasible method for evaluating the antitumor properties of compounds and could be applied for new drug discovery.
Review
Biochemistry & Molecular Biology
Shirin Hafezi, Maha Saber-Ayad, Wael M. Abdel-Rahman
Summary: The RAS gene family, especially KRAS, is the most frequently mutated oncogene family in human cancer history, with a significant impact on pancreatic cancer progression. Studying the function of KRAS and its mutations in the tumor microenvironment is crucial for understanding pancreatic cancer and developing novel therapeutic strategies.ongoing clinical trials are using the KRAS oncogene signaling network as therapeutic targets, in addition to exploring the link between diabetes and PDAC, and the potential role of vitamin D in TME modulation for the treatment of PDAC.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Imayavaramban Lakshmanan, Saravanakumar Marimuthu, Sanjib Chaudhary, Parthasarathy Seshacharyulu, Satyanarayana Rachagani, Sakthivel Muniyan, Ramakanth Chirravuri-Venkata, Pranita Atri, Sanchita Rauth, Rama Krishna Nimmakayala, Jawed Akhtar Siddiqui, Shailendra K. Gautam, Ashu Shah, Gopalakrishnan Natarajan, Seema Parte, Namita Bhyravbhatla, Kavita Mallya, Dhanya Haridas, Geoffrey A. Talmon, Lynette M. Smith, Sushil Kumar, Apar Kishor Ganti, Maneesh Jain, Moorthy P. Ponnusamy, Surinder K. Batra
Summary: Muc16 plays an oncogenic role in pancreatic ductal adenocarcinoma (PDAC). Deletion of Muc16 can decrease tumor progression and improve overall survival in mice models. Muc16 knockout reduces tumor microenvironment factors and incidence of liver and lung metastasis. Further research shows that Muc16 alters the expression of Actg2, Myh11, and Pdlim3 genes, affecting pancreatic cancer progression and metastasis.
Article
Chemistry, Multidisciplinary
Qian-Zhi Ni, Bing Zhu, Yan Ji, Qian-Wen Zheng, Xin Liang, Ning Ma, Hao Jiang, Feng-Kun Zhang, Yu-Rong Shang, Yi-Kang Wang, Sheng Xu, Er-Bin Zhang, Yan-Mei Yuan, Tian-Wei Chen, Fen-Fen Yin, Hui-Jun Cao, Jing-Yi Huang, Ji Xia, Xu-Fen Ding, Xiao-Song Qiu, Kai Ding, Chao Song, Wen-Tao Zhou, Meng Wu, Kang Wang, Rui Lui, Qiu Lin, Wei Chen, Zhi-Gang Li, Shu-Qun Cheng, Xiao-Fan Wang, Dong Xie, Jing-Jing Li
Summary: This study reveals that PPDPF functions as an important regulator of SOS1 and promotes tumor development in pancreatic ductal adenocarcinoma (PDAC) through the PPDPF-SOS1 axis. This finding provides a potential therapeutic target for PDAC.
Article
Oncology
Sami Shoucair, Joseph R. Habib, Ning Pu, Benedict Kinny-Koster, A. Floortje van Ooston, Ammar A. Javed, Kelly J. Lafaro, Jin He, Christopher L. Wolfgang, Jun Yu
Summary: The study revealed that combinations of mutations in the four driver genes are associated with prognosis in resected PDAC patients. Patients with combined mtKRAS and mtTP53 had a better overall survival and recurrence-free survival when the KRAS p.G12D variant was present.
ANNALS OF SURGICAL ONCOLOGY
(2022)
Article
Oncology
Ayelet Shai, Evleen Galouk, Reem Miari, Hala Tareef, Marei Sammar, Mouhammad Zeidan, Anwar Rayan, Mizied Falah
Summary: KRAS mutations play a crucial role in lethal pancreatic adenocarcinomas. In this study, the use of PNAs to target the mutated KRAS gene resulted in inhibition of cancer cell growth and induction of apoptosis. This therapeutic approach shows promise as a novel drug for targeting KRAS-driven cancers.