Article
Oncology
Wenfang Zheng, Zhiyi Yang, Ping Song, Yingchao Sun, Pan Liu, Lei Yue, Kaiqi Lv, Xinjie Wang, Yuqin Shen, Jianmin Si, Xue Zhang, Yuehai Ke, Hongqiang Cheng, Weiling Hu
Summary: This study found that adaptive resistance occurs in KRAS-mutant gastric cancer cells treated with MEK inhibitors. The combination of SHP099 and AZD6244 showed significant efficacy in treating xenografts. Mechanistically, SHP2 activates KSR1 to promote adaptive resistance. Therefore, the combination of selumetinib and SHP099 may be an effective therapeutic strategy for KRAS-mutant gastric cancers.
Article
Pharmacology & Pharmacy
Juanjuan Feng, Zhengke Lian, Xinting Xia, Yue Lu, Kewen Hu, Yunpeng Zhang, Yanan Liu, Longmiao Hu, Kun Yuan, Zhenliang Sun, Xiufeng Pang
Summary: It is found that KRAS-mutant non-small cell lung cancer (NSCLC) is resistant to MEK inhibitors due to the activation of mitochondrial oxidative phosphorylation (OX-PHOS), and the co-administration of trametinib and IACS-010759 can effectively inhibit tumor growth and prolong mouse survival.
ACTA PHARMACEUTICA SINICA B
(2023)
Review
Immunology
Xuan Wu, Wenping Song, Cheng Cheng, Ziyang Liu, Xiang Li, Yu Cui, Yao Gao, Ding Li
Summary: Three isoforms of RAS gene, KRAS, NRAS, and HRAS, are the most mutated family of small GTPases in cancer. While targeted immunotherapies have improved the survival of patients with non-KRAS-mutant cancer, RAS-mutant cancers still have a poor prognosis due to their high aggressiveness. However, recent advances in the use of allele-specific covalent inhibitors have led to the development of effective pharmacological interventions against RAS-mutant cancer, such as Sotorasib (AMG510) for KRAS-G12C mutant NSCLC. This review summarizes the progress and promise of small-molecule inhibitors in clinical trials to improve the prognosis of tumors with RAS mutations.
FRONTIERS IN IMMUNOLOGY
(2023)
Editorial Material
Oncology
Christina Guo, Udai Banerji
Summary: KRAS mutations play a critical role in cancer, with drugs targeting KRAS(G12C) mutations showing potential efficacy. Clinical trials targeting non-G12C mutated KRAS driven cancers with the dual RAF-MEK inhibitor VS-6766 have shown early single agent activity.
BRITISH JOURNAL OF CANCER
(2021)
Article
Pharmacology & Pharmacy
Nai-jie Fu, Rui-ying Xi, Xiao-ke Shi, Run-ze Li, Zhong-hui Zhang, Ling-yu Li, Guo-lin Zhang, Fei Wang
Summary: KRAS mutations play a crucial role in NSCLC, and the SHP2 inhibitor HCP shows potential therapeutic effects by inhibiting SHP2 to control cell proliferation and metastasis.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Chune Yu, Dan Luo, Jing Yu, Min Zhang, Xiaobo Zheng, Guangchao Xu, Jiaxin Wang, Huiling Wang, Yufei Xu, Ke Jiang, Jie Xu, Xuelei Ma, Jing Jing, Hubing Shi
Summary: The study identified GRB7-PLK1 as a crucial axis mediating RTKs, resulting in tolerance to MEK inhibitors. Therefore, PLK1 is a promising target for enhancing the clinical treatment of CRC patients with KRAS mutations by synergizing with MEK inhibitors.
Article
Cell Biology
Xiaofei Zhang, Tiebo Mao, Haiyan Xu, Shumin Li, Ming Yue, Jingyu Ma, Jiayu Yao, Yongchao Wang, Xiao Zhang, Weiyu Ge, Yanling Wang, Daiyuan Shentu, Liwei Wang
Summary: The combination treatment of Trametinib and JQ1 shows synergistic effects in KRAS mutant pancreatic cancer cells, inhibiting cell proliferation. Moreover, the combination therapy may induce different cell death modes in different pancreatic cancer subtypes.
Article
Multidisciplinary Sciences
David H. Peng, B. Leticia Rodriguez, Lixia Diao, Pierre-Olivier Gaudreau, Aparna Padhye, Jessica M. Konen, Joshua K. Ochieng, Caleb A. Class, Jared J. Fradette, Laura Gibson, Limo Chen, Jing Wang, Lauren A. Byers, Don L. Gibbons
Summary: Understanding the resistance mechanisms in mutant KRAS lung cancers to targeted therapies and immune checkpoint blockade is crucial for developing novel combination therapies. MEK inhibition combined with anti-PD-L1 can synergistically reduce lung tumor growth, but resistance may develop eventually. Increased Th17 cell infiltration in resistant tumors promotes invasiveness and resistance to MEK inhibitors, and a triple therapy targeting MEK, PD-L1, and IL-17 may overcome this resistance for better in vivo responses.
NATURE COMMUNICATIONS
(2021)
Review
Chemistry, Medicinal
Claudia Korzeniecki, Ronny Priefer
Summary: KRAS genes are commonly mutated in cancer, and targeting KRAS mutant cancers has proven difficult due to lack of success with direct inhibitors. Researchers are now focusing on targeting other areas of the MAPK signaling pathway to inhibit KRAS function.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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.
Article
Oncology
Susmita Ghosh, Fan Fan, Reid T. Powell, Jason Roszik, Yong Sung Park, Clifford Stephan, Manu Sebastian, Lin Tan, Alexey Sorokin, Philip L. Lorenzi, Scott Kopetz, Lee M. Ellis, Rajat Bhattacharya
Summary: Mutations in KRAS are common in metastatic colorectal cancer (mCRC) and direct targeting of these mutations is difficult. In this study, we found that the combination of trametinib and vincristine showed significant efficacy in inhibiting tumor growth and inducing apoptosis in KRAS-mutant colorectal cancer. The combination also inhibited the RAS-RAF-MEK and PI3K-AKT-mTOR survival pathways.
MOLECULAR CANCER THERAPEUTICS
(2023)
Article
Oncology
Thomas McFall, Michael Trogdon, Anita C. Guizar, John F. Langenheim, Laura Sisk-Hackworth, Edward C. Stites
Summary: The combination of KRAS G12C inhibitors with EGFR inhibitors has shown consistent benefits, including inhibiting both wild-type and mutant RAS.
NPJ PRECISION ONCOLOGY
(2022)
Article
Oncology
Bob Meeusen, Emanuela Elsa Cortesi, Judit Domenech Omella, Anna Sablina, Juan-Jose Ventura, Veerle Janssens
Summary: This study found that the loss of PP2A activator PTPA in KRAS-mutant lung adenocarcinomas is associated with poorer overall survival, increased cell growth, and accelerated tumor formation. Additionally, the depletion of PPP2R4 induced resistance against MEK inhibitor but sensitized cells to mTOR inhibitor, highlighting its clinical relevance in NSCLC etiology and kinase inhibitor response.
Article
Cell Biology
Rongjie Cheng, Fanying Li, Maolei Zhang, Xin Xia, Jianzhuang Wu, Xinya Gao, Huangkai Zhou, Zhi Zhang, Nunu Huang, Xuesong Yang, Yaliang Zhang, Shunli Shen, Tiebang Kang, Zexian Liu, Feizhe Xiao, Hongwei Yao, Jianbo Xu, Chao Yan, Nu Zhang
Summary: This study identifies RASON as a positive regulator of oncogenic RAS signaling and reveals its aberrant overexpression in pancreatic ductal adenocarcinoma. RASON promotes tumor cell proliferation and tumor growth by sustaining the hyperactive state of KRAS through inhibiting GTP hydrolysis. Deprivation of RASON sensitizes KRAS mutant pancreatic cancer cells to EGFR inhibitors.
Article
Immunology
Shengyun Zhu, Kairen Xu, Shuyao Li, Xiangru Yu, Yahui Liu, Qigang Zhang, Lingyu Zeng, Kailin Xu, Chunling Fu
Summary: This study investigates the impact of the MPLW515L mutation on intestinal homeostasis in a mutated MPN mice model. The mutation aggravates inflammation, decreases the levels of tight junction proteins and receptors for bacteria metabolites, and increases the activation of the caspase1/IL-1 beta signaling pathway. Additionally, the mutation leads to upexpression of anti-microbial genes in the intestinal tract.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2023)
Article
Oncology
J. Akutagawa, T. Q. Huang, I. Epstein, T. Chang, M. Quirindongo-Crespo, C. L. Cottonham, M. Dail, B. S. Slusher, L. S. Friedman, D. Sampath, B. S. Braun
Article
Biochemistry & Molecular Biology
E. J. Pomeroy, L. A. Lee, R. D. W. Lee, D. K. Schirm, N. A. Temiz, J. Ma, T. A. Gruber, E. Diaz-Flores, B. S. Moriarity, J. R. Downing, K. M. Shannon, D. A. Largaespada, C. E. Eckfeldt
Article
Multidisciplinary Sciences
Elliot Stieglitz, Tali Mazor, Adam B. Olshen, Huimin Geng, Laura C. Gelston, Jon Akutagawa, Daniel B. Lipka, Christoph Plass, Christian Flotho, Farid F. Chehab, Benjamin S. Braun, Joseph F. Costello, Mignon L. Loh
NATURE COMMUNICATIONS
(2017)
Letter
Hematology
Elliot Stieglitz, Y. Lucy Liu, Peter D. Emanuel, Robert P. Castleberry, Todd M. Cooper, Kevin M. Shannon, Mignon L. Loh
Editorial Material
Hematology
Kevin Shannon, Michelle Hermiston
Article
Hematology
Elliot Stieglitz, Camille B. Troup, Laura C. Gelston, John Haliburton, Eric D. Chow, Kristie B. Yu, Jon Akutagawa, Amaro N. Taylor-Weiner, Y. Lucy Liu, Yong-Dong Wang, Kyle Beckman, Peter D. Emanuel, Benjamin S. Braun, Adam Abate, Robert B. Gerbing, Todd A. Alonzo, Mignon L. Loh
Article
Hematology
Zohar Sachs, Rebecca S. LaRue, Hanh T. Nguyen, Karen Sachs, Klara E. Noble, Nurul Azyan Mohd Hassan, Ernesto Diaz-Flores, Susan K. Rathe, Aaron L. Sarver, Sean C. Bendall, Ngoc A. Ha, Miechaleen D. Diers, Garry P. Nolan, Kevin M. Shannon, David A. Largaespada
Article
Hematology
Michael R. Burgess, Eugene Hwang, Ari J. Firestone, Tannie Huang, Jin Xu, Johannes Zuber, Natacha Bohin, Tiffany Wen, Scott C. Kogan, Kevin M. Haigis, Deepak Sampath, Scott Lowe, Kevin Shannon, Qing Li
Article
Oncology
Chong Chen, Yu Liu, Amy R. Rappaport, Thomas Kitzing, Nikolaus Schultz, Zhen Zhao, Aditya S. Shroff, Ross A. Dickins, Christopher R. Vakoc, James E. Bradner, Wendy Stock, Michelle M. LeBeau, Kevin M. Shannon, Scott Kogan, Johannes Zuber, Scott W. Lowe
Article
Medicine, Research & Experimental
Tiffany Chang, Kimberly Krisman, Emily Harding Theobald, Jin Xu, Jon Akutagawa, Jennifer O. Lauchle, Scott Kogan, Benjamin S. Braun, Kevin Shannon
JOURNAL OF CLINICAL INVESTIGATION
(2013)
Article
Multidisciplinary Sciences
Monique Dail, Jason Wong, Jessica Lawrence, Daniel O'Connor, Joy Nakitandwe, Shann-Ching Chen, Jin Xu, Leslie B. Lee, Keiko Akagi, Qing Li, Jon C. Aster, Warren S. Pear, James R. Downing, Deepak Sampath, Kevin Shannon
Article
Biochemistry & Molecular Biology
Ernesto Diaz-Flores, Hana Goldschmidt, Philippe Depeille, Victor Ng, Jon Akutagawa, Kimberly Krisman, Michael Crone, Michael R. Burgess, Olusegun Williams, Benjamin Houseman, Kevan Shokat, Deepak Sampath, Gideon Bollag, Jeroen P. Roose, Benjamin S. Braun, Kevin Shannon
Article
Oncology
Ernesto Diaz-Flores, Evan Q. Comeaux, Kailyn L. Kim, Ella Melnik, Kyle Beckman, Kara L. Davis, Kevin Wu, Jon Akutagawa, Olga Bridges, Roberta Marino, Margo Wohlfeil, Benjamin S. Braun, Charles G. Mullighan, Mignon L. Loh
Letter
Hematology
Thai Hoa Tran, Jonathan Nguyen, Adrian Stecula, Jon Akutagawa, Anthony Moorman, Benjamin S. Braun, Andrej Sali, Charles G. Mullighan, Neil P. Shah, Yunfeng Dai, Meenakshi Devidas, Kathryn G. Roberts, Catherine C. Smith, Mignon L. Loh