Review
Health Care Sciences & Services
Darren Cowzer, Mohammed Zameer, Michael Conroy, Walter Kolch, Austin G. Duffy
Summary: This article reviews therapeutic innovations targeting RAS signaling in pancreatic cancer from a clinical perspective. Despite the strong resistance of pancreatic cancer to treatment, new approaches such as inhibiting mutated KRAS, KRAS activators, and effectors show promise in breaking this therapeutic deadlock.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Medicine, General & Internal
J. H. Strickler, H. Satake, T. J. George, R. Yaeger, A. Hollebecque, I Garrido-Laguna, M. Schuler, T. F. Burns, A. L. Coveler, G. S. Falchook, M. Vincent, Y. Sunakawa, L. Dahan, D. Bajor, S-Y Rha, C. Lemech, D. Juric, M. Rehn, G. Ngarmchamnanrith, P. Jafarinasabian, Q. Tran, D. S. Hong
Summary: This study evaluated the safety and efficacy of sotorasib in patients with KRAS p.G12C-mutated pancreatic cancer who had previously received treatment. The results showed that sotorasib demonstrated anticancer activity and had an acceptable safety profile in these patients.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Han Yan, Chih-Chieh Yu, Stuart A. Fine, Ayman Lee Youssof, Ye-Ran Yang, Jun Yan, Dillon C. Karg, Edwin C. Cheung, Richard A. Friedman, Haoqiang Ying, Emily Chen, Ji Luo, Yi Miao, Wanglong Qiu, Gloria H. Su
Summary: The restoration of wild-type KRAS expression in human PDAC cell lines significantly attenuates malignancy, positively regulating the HIPPO signaling pathway. In contrast, loss of wild-type KRAS leads to functional activation of YAP1 and enhanced tumor malignancy in PDAC cells, providing insights into therapeutic strategies targeting KRAS.
Article
Oncology
Philip A. Philip, Ibrahim Azar, Joanne Xiu, Michael J. Hall, Andrew Eugene Hendifar, Emil Lou, Jimmy J. Hwang, Jun Gong, Rebecca Feldman, Michelle Ellis, Phil Stafford, David Spetzler, Moh'd M. Khushman, Davendra Sohal, A. Craig Lockhart, Benjamin A. Weinberg, Wafi k S. El-Deiry, John Marshall, Anthony F. Shields, W. Michael Korn
Summary: KRAS WT PDAC represents 10.7% of PDAC and is enriched with potential pathogenic drivers and better treatment prognosis. Identifying KRAS WT patients can expand therapeutic options in clinical practice.
CLINICAL CANCER RESEARCH
(2022)
Article
Cell Biology
Cheng-Yao Chiang, Songqing Fan, Hongmei Zheng, Wenjun Guo, Zehan Zheng, Yihua Sun, Chuanqi Zhong, Juan Zeng, Shuaihu Li, Min Zhang, Tian Xiao, Duo Zheng
Summary: This study reveals the tumor-suppressive role of SETD7 in non-small cell lung cancer (NSCLC) by modulating KRAS methylation and degradation. SETD7 interacts with KRAS and methylates KRAS at lysines 182 and 184, leading to KRAS degradation and attenuation of the RAS/MEK/ERK signaling cascade.
Review
Oncology
Noah C. Cheng, Robert H. Vonderheide
Summary: The long-held desire to target the mutant KRAS gene therapeutically is being fulfilled with the development of small-molecule inhibitors. In addition to its role as a therapeutic target, KRAS also plays a crucial role in shaping the immunosuppressive nature of the tumor microenvironment. This opens up new possibilities for combination immunotherapy using mKRAS inhibitors.
Editorial Material
Medicine, General & Internal
Cornelis J. M. Melief
Summary: Pancreatic ductal adenocarcinoma is the deadliest of all common cancers. The study reported remarkable deep and durable tumor shrinkage in a heavily pretreated patient who received an infusion of autologous T cells transduced.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Oncology
Asimina Koulouridi, Michaela Karagianni, Ippokratis Messaritakis, Maria Sfakianaki, Alexandra Voutsina, Maria Trypaki, Maria Bachlitzanaki, Evangelos Koustas, Michalis Karamouzis, Anastasios Ntavatzikos, Anna Koumarianou, Nikolaos Androulakis, Dimitrios Mavroudis, Maria Tzardi, John Souglakos
Summary: The study reveals that KRAS G12D mutation is associated with better overall survival, while KRAS G12C mutation may indicate worse prognosis in terms of progression-free and overall survival. KRAS exon 3 and exon 4 mutations also have different impacts on progression-free and overall survival.
Article
Multidisciplinary Sciences
Irene Ischenko, Stephen D'Amico, Manisha Rao, Jinyu Li, Michael J. Hayman, Scott Powers, Oleksi Petrenko, Nancy C. Reich
Summary: In established KRAS-driven pancreatic cancer, KRAS ablation does not impact intrinsic tumorigenic capacity but triggers an antitumor immune response, highlighting the significance of KRAS-driven immune suppression in tumor maintenance.
NATURE COMMUNICATIONS
(2021)
Review
Oncology
Lisa Maria Mustachio, Anca Chelariu-Raicu, Lorant Szekvolgyi, Jason Roszik
Summary: KRAS, mutated in 25% of human cancers, is crucial for tumorigenesis. Despite difficulties in directly targeting it, success has been found in targeting other proteins in the RAS pathway. Recent findings suggest progress towards developing a direct KRAS inhibitor, highlighting the need for continued research for an optimal treatment for certain tumor types.
Review
Oncology
Ji Luo
Summary: Pancreatic cancer is a difficult-to-treat cancer with low survival rates, commonly driven by oncogenic mutations in the KRAS gene. Therapeutic strategies targeting mutant KRAS show promise but face challenges in achieving clinical efficacy.
SEMINARS IN ONCOLOGY
(2021)
Article
Engineering, Biomedical
Ri Huang, Hong Du, Liang Cheng, Peizhuo Zhang, Fenghua Meng, Zhiyuan Zhong
Summary: In this study, cRGD peptide-modified bioresponsive chimaeric polymersomes (cRGD-BCP) were used for efficient delivery of siKRAS to PANC-1 tumor cells, resulting in potent silencing of KRAS G12D mRNA and effective suppression of pancreatic cancer tumor growth in mice. The density of cRGD greatly impacted the uptake and silencing efficiency of cRGD-BCP-siKRAS. cRGD-BCP-siKRAS significantly enhanced the uptake of siKRAS in PANC-1 tumor and achieved remarkable tumor inhibition and survival benefits.
ACTA BIOMATERIALIA
(2023)
Article
Multidisciplinary Sciences
Junko Tanaka, Tatsuo Nakagawa, Kunio Harada, Chigusa Morizane, Hidenori Tanaka, Satoshi Shiba, Akihiro Ohba, Susumu Hijioka, Erina Takai, Shinichi Yachida, Yoshio Kamura, Takeshi Ishida, Takahide Yokoi, Chihiro Uematsu
Summary: By improving the detection efficiency and accuracy of multiplex dPCR with melting curve analysis, we were able to detect and genotype KRAS mutations in circulating tumor DNA (ctDNA) with greater sensitivity. Our study also showed a high detection rate of KRAS mutations in patients with liver or lung metastasis, consistent with previous reports. Therefore, multiplex dPCR with melting curve analysis has demonstrated clinical utility in the detection and genotyping of ctDNA.
SCIENTIFIC REPORTS
(2023)
Article
Cell Biology
Mario A. Shields, Christina Spaulding, Anastasia E. Metropulos, Mahmoud G. Khalafalla, Thao N. D. Pham, Hidayatullah G. Munshi
Summary: Ga13 functions as a tumor suppressor in lymphomas, but its role in epithelial cancers remains unclear. Loss of Ga13 in KPC GEM model promotes well-differentiated tumors and reduces survival. Tumors with low Ga13 expression exhibit increased E-cadherin expression and mTOR signaling.
Article
Biotechnology & Applied Microbiology
Tatsunori Suzuki, Takahiro Kishikawa, Tatsuyuki Sato, Norihiko Takeda, Yuki Sugiura, Takahiro Seimiya, Kazuma Sekiba, Motoko Ohno, Takuma Iwata, Rei Ishibashi, Motoyuki Otsuka, Kazuhiko Koike
Summary: Mutational activation of the KRAS gene is an early event in the carcinogenesis of almost all PDAC. Research shows that KRAS mutation increases the dependency on glucose and glutamine and reduces intracellular levels of amino acids, necessitating higher autophagic flux for cell viability.
CANCER GENE THERAPY
(2022)
