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
Oncology
Bin Yang, Xi Li, Yu Fu, Ensong Guo, Youqiong Ye, Fuxia Li, Si Liu, Rourou Xiao, Chen Liu, Funian Lu, Jia Huang, Tianyu Qin, Leng Han, Guang Peng, Gordon B. Mills, Chaoyang Sun, Gang Chen
Summary: This study demonstrates that the combination of MEK inhibitors with PARP inhibitors and anti-PD-L1 can significantly inhibit tumor growth in mutant KRAS tumors by triggering DNA damage, activating immune responses, and reducing myeloid-derived suppressor cell infiltration.
Article
Oncology
Jingtai Zhi, Jiaoyu Yi, Xiukun Hou, Wei Wang, Weiwei Yang, Linfei Hu, Jianfeng Huang, Shicheng Guo, Xianhui Ruan, Ming Gao, Xiangqian Zheng
Summary: In this study, RTKs activation was found to lead to reactivation of the MAPK pathway and resistance to MEKi in differentiated thyroid carcinoma, which was reversed by SHP2 blockade. Combination therapy with SHP099, a novel active inhibitor of SHP2, and MEKi showed promising therapeutic effects for advanced thyroid carcinoma and MEKi-resistant cases.
AMERICAN JOURNAL OF CANCER RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Beike Wang, Wei Zhang, Gao Zhang, Lawrence Kwong, Hezhe Lu, Jiufeng Tan, Norah Sadek, Min Xiao, Jie Zhang, Marilyne Labrie, Sergio Randell, Aurelie Beroard, Eric Sugarman, Vito W. Rebecca, Zhi Wei, Yiling Lu, Gordon B. Mills, Jeffrey Field, Jessie Villanueva, Xiaowei Xu, Meenhard Herlyn, Wei Guo
Summary: The study focuses on utilizing a combination of BRAF and MEK inhibitors to target the MAPK pathway in treating melanoma, with findings showing the crucial role of the mTORC1 signaling pathway in mediating drug resistance. Interestingly, some resistant melanoma cells are sensitive to mTORC1 inhibition, indicating the importance of mTOR activation in melanoma resistance to MAPK inhibitors.
Article
Cell Biology
Vrushank Bhatt, Taijin Lan, Wenping Wang, Jerry Kong, Eduardo Cararo Lopes, Jianming Wang, Khoosheh Khayati, Akash Raju, Michael Rangel, Enrique Lopez, Zhixian Sherrie Hu, Xuefei Luo, Xiaoyang Su, Jyoti Malhotra, Wenwei Hu, Sharon R. Pine, Eileen White, Jessie Yanxiang Guo
Summary: LKB1 and KRAS co-mutations in NSCLC lead to aggressive tumor growth. Inhibition of autophagy and MEK pathway may be a potential therapeutic strategy for NSCLC with LKB1 and KRAS co-mutations.
CELL DEATH & DISEASE
(2023)
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)
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
Oncology
Emeric Limagne, Lisa Nuttin, Marion Thibaudin, Elise Jacquin, Romain Aucagne, Marjorie Bon, Solene Revy, Robby Barnestein, Elise Ballot, Caroline Truntzer, Valentin Derangere, Jean-David Fumet, Charlene Latour, Cedric Rebe, Pierre-Simon Bellaye, Coureche-Guillaume Kaderbhai, Aodrenn Spill, Bertrand Collin, Mary B. Callanan, Aurelie Lagrange, Laure Favier, Bruno Coudert, Laurent Arnould, Sylvain Ladoire, Bertrand Routy, Philippe Joubert, Francois Ghiringhelli
Summary: Chemotherapy combined with MEK inhibitor enhances the sensitivity of lung cancer cells to immune checkpoint inhibitors by inducing CXCL10 expression and CD8(+) T cell recruitment. The study also highlights the role of TLR9- and OPTN-dependent mitophagy in enhancing the efficacy of chemoimmunotherapy.
Article
Oncology
Yihui Gu, Chengjiang Wei, Manhon Chung, Haibo Li, Zizhen Guo, Manmei Long, Yuehua Li, Wei Wang, Rehanguli Aimaier, Qingfeng Li, Zhichao Wang
Summary: In this study, MEKi-resistant cell models were generated and the mechanisms of MEKi resistance were investigated using high-throughput transcriptomic sequencing. The upregulation of LAMA4/ITGB1/FAK/SRC signaling was found to contribute to MEKi resistance in MPNST cells. Concurrent inhibition of MAPK signaling and FAK/SRC cascade could enhance the sensitivity of MPNST cells to MEKi.
FRONTIERS IN ONCOLOGY
(2022)
Review
Chemistry, Medicinal
Tingkai Chen, Xu Tang, Zhenqi Wang, Feng Feng, Chunlei Xu, Qun Zhao, Yulan Wu, Haopeng Sun, Yao Chen
Summary: This review provides a comprehensive overview of the structure, biological function, and regulation of SOS1, a potential therapeutic target for KRAS-mutant cancers. It also highlights recent advances in SOS1 inhibitors, including their binding modes, structure-activity relationships, and pharmacological activities.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Editorial Material
Oncology
Yulei Zhao, Jenny Y. Xue, Piro Lito
Summary: Researchers have discovered a selective inhibitor targeting GEF SOS1, which effectively suppresses the growth of KRAS-mutant tumors.
Article
Oncology
Yixuan Ma, Benjamin Schulz, Nares Trakooljul, Moosheer Al Ammar, Anett Sekora, Sina Sender, Frieder Hadlich, Dietmar Zechner, Frank Ulrich Weiss, Markus M. Lerch, Robert Jaster, Christian Junghanss, Hugo Murua Escobar
Summary: Small molecule inhibitors and targeted therapy have significant potential for pancreatic ductal adenocarcinoma (PDAC) treatment. The study found that two KRAS inhibitors, BI-3406 and sotorasib, demonstrated different anti-tumor efficacy and displayed synergistic or additive effects when combined with downstream inhibitors, emphasizing the importance of KRAS as a therapeutic target for PDAC.
Article
Pharmacology & Pharmacy
Ye Li, Yuncang Yuan, Fan Zhang, Aizhen Guo, Fuao Cao, Mengmeng Song, Yating Fu, Xiaowen Xu, Hao Shen, Shangyong Zheng, Yamin Pan, Wenjun Chang
Summary: Our study found that frequent resistance to SHP2 inhibitors exists in colorectal carcinoma cells, even in those without RAS mutations. Rapid adaptive reactivation of the AKT pathway in response to SHP2 inhibition may contribute to this resistance, driven by the reactivation of RTKs or released p-FAK. Co-inhibition of FAK abrogated the feedback reactivation of AKT in response to SHP2 inhibition, leading to sustained AKT pathway suppression and improved antitumor efficacy.
FRONTIERS IN PHARMACOLOGY
(2021)
Review
Oncology
Yuta Adachi, Ryo Kimura, Kentaro Hirade, Hiromichi Ebi
Summary: Mutant KRAS-driven tumor cells can become independent of mutant KRAS by activating alternative pathways, leading to a mesenchymal phenotype and potential metastasis. YAP and/or RSK-mTOR pathway activation, along with mutations in LKB1, KEAP1, and/or NRF2, are linked to mutant KRAS autonomy. Understanding KRAS dependency is crucial for selecting patients for mutant-specific inhibitors, while investigating mechanisms of KRAS autonomy is important for developing optimal treatment strategies for KRAS-independent tumors.
Article
Oncology
Yutuan Wu, Jie Huang, Cristina Ivan, Yunjie Sun, Shaolin Ma, Lingegowda S. Mangala, Bryan M. Fellman, Diana L. Urbauer, Nicholas B. Jennings, Prahlad Ram, Robert L. Coleman, Wei Hu, Anil K. Sood
Summary: The study revealed that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells, and EphrinA1-mediated MEK inhibition can overcome resistance. Dual targeting of EphA2 and MEK, along with chemotherapy, should be considered for future clinical development.
GYNECOLOGIC ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Michelle Fodor, Edmund Price, Ping Wang, Hengyu Lu, Andreea Argintaru, Zhouliang Chen, Meir Glick, Huai-Xiang Hao, Mitsunori Kato, Robert Koenig, Jonathan R. LaRochelle, Gang Liu, Eric McNeill, Dyuti Majumdar, Gisele A. Nishiguchi, Lawrence B. Perez, Gregory Paris, Christopher M. Quinn, Timothy Ramsey, Martin Sendzik, Michael David Shultz, Sarah L. Williams, Travis Stams, Stephen C. Blacklow, Michael G. Acker, Matthew J. LaMarche
ACS CHEMICAL BIOLOGY
(2018)
Article
Oncology
Patrick Kwok-Shing Ng, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta, Zixing Wang, Venkata Hemanjani Bhavana, Richard Tran, Stephanie Soewito, Darlan Conterno Minussi, Daniela Moreno, Kathleen Kong, Turgut Dogruluk, Hengyu Lu, Jianjiong Gao, Collin Tokheim, Daniel Cui Zhou, Amber M. Johnson, Jia Zeng, Carman Ka Man Ip, Zhenlin Ju, Matthew Wester, Shuangxing Yu, Yongsheng Li, Christopher P. Vellano, Nikolaus Schultz, Rachel Karchin, Li Ding, Yiling Lu, Lydia Wai Ting Cheung, Ken Chen, Kenna R. Shaw, Funda Meric-Bernstam, Kenneth L. Scott, Song Yi, Nidhi Sahni, Han Liang, Gordon B. Mills
Article
Multidisciplinary Sciences
Caitlin L. Grzeskowiak, Samrat T. Kundu, Xiulei Mo, Andrei A. Ivanov, Oksana Zagorodna, Hengyu Lu, Richard H. Chapple, Yiu Huen Tsang, Daniela Moreno, Maribel Mosqueda, Karina Eterovic, Jared J. Fradette, Sumreen Ahmad, Fengju Chen, Zechen Chong, Ken Chen, Chad J. Creighton, Haian Fu, Gordon B. Mills, Don L. Gibbons, Kenneth L. Scott
NATURE COMMUNICATIONS
(2018)
Meeting Abstract
Oncology
Michelle Fodor, Edmund Price, Ping Wang, Hengyu Lu, Andreea Argintaru, Zhouliang Chen, Meir Glick, Huai-Xiang Hao, Mitsunori Kato, Robert Koenig, Jonathan R. LaRochelle, Gang Liu, Eric McNeill, Dyuti Majumdar, Gisele Nishiguchi, Lawrence Perez, Greg Paris, Christopher Quinn, Timothy Ramsey, Martin Sendzik, Michael Shultz, Sarah Williams, Travis Stams, Stephen C. Blacklow, Matthew J. LaMarche, Michael G. Acker
Article
Oncology
Huai-Xiang Hao, Hongyun Wang, Chen Liu, Steven Kovats, Roberto Velazquez, Hengyu Lu, Bhavesh Pant, Matthew Shirley, Matthew J. Meyer, Minying Pu, Joanne Lim, Michael Fleming, Leigh Ann Alexander, Ali Farsidjani, Matthew J. LaMarche, Susan Moody, Serena J. Silver, Giordano Caponigro, Darrin D. Stuart, Tinya J. Abrams, Peter S. Hammerman, Juliet Williams, Jeffrey A. Engelman, Silvia Goldoni, Morvarid Mohseni
MOLECULAR CANCER THERAPEUTICS
(2019)
Article
Biology
Yiu Huen Tsang, Yumeng Wang, Kathleen Kong, Caitlin Grzeskowiak, Oksana Zagorodna, Turgut Dogruluk, Hengyu Lu, Nicole Villafane, Venkata Hemanjani Bhavana, Daniela Moreno, Sarah H. Elsea, Han Liang, Gordon B. Mills, Kenneth L. Scott
Article
Oncology
Chen Liu, Hengyu Lu, Hongyun Wang, Alice Loo, Xiamei Zhang, Guizhi Yang, Colleen Kowal, Scott Delach, Ye Wang, Silvia Goldoni, William D. Hastings, Karrie Wong, Hui Gao, Matthew J. Meyer, Susan E. Moody, Matthew J. LaMarche, Jeffrey A. Engelman, Juliet A. Williams, Peter S. Hammerman, Tinya J. Abrams, Morvarid Mohseni, Giordano Caponigro, Huai-Xiang Hao
Summary: The study evaluated the efficacy and synergistic mechanisms of a novel SHP2 inhibitor, TNO155, in combination with various drugs in different cancer models. Results demonstrated that TNO155 effectively blocks tumor-promoting and immune-suppressive RTK signaling, providing a rationale for clinical evaluation of these combinations.
CLINICAL CANCER RESEARCH
(2021)
Article
Multidisciplinary Sciences
Jun Li, Hengyu Lu, Patrick Kwok-Shing Ng, Angeliki Pantazi, Carman Ka Man Ip, Kang Jin Jeong, Bianca Amador, Richard Tran, Yiu Huen Tsang, Lixing Yang, Xingzhi Song, Turgut Dogruluk, Xiaojia Ren, Angela Hadjipanayis, Christopher A. Bristow, Semin Lee, Melanie Kucherlapati, Michael Parfenov, Jiabin Tang, Sahil Seth, Harshad S. Mahadeshwar, Kamalika Mojumdar, Dong Zeng, Jianhua Zhang, Alexei Protopopov, Jonathan G. Seidman, Chad J. Creighton, Yiling Lu, Nidhi Sahni, Kenna R. Shaw, Funda Meric-Bernstam, Andrew Futreal, Lynda Chin, Kenneth L. Scott, Raju Kucherlapati, Gordon B. Mills, Han Liang
Summary: The study introduces a new method to systematically identify fusion genes and evaluate their sensitivity to drugs, revealing that some of these genes have activating effects on tumor growth. It proposes an integrated, level-of-evidence classification system to prioritize gene fusions systematically.
Meeting Abstract
Oncology
Fabio Savarese, Andreas Gollner, Dorothea Rudolph, Jesse Lipp, Johannes Popow, Marco H. Hofmann, Heribert Arnhof, Joerg Rinnenthal, Francesca Trapani, Michael Gmachl, Daniel Gerlach, Joachim Broeker, Peter Ettmayer, Andreas Mantoulidis, Jason Phan, Christian A. Smethurst, Matthias Treu, Alex G. Waterson, Hengyu Lu, Annette Machado, Joseph Daniele, Stephan W. Fesik, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek, Darryl B. McConnell, Mark Petronczki, Norbert Kraut, Irene C. Waizenegger
Meeting Abstract
Oncology
Marco H. Hofmann, Hengyu Lu, Ulrich Duenzinger, Daniel Gerlach, Francesca Trapani, Annette A. Machado, Joseph R. Daniele, Irene Waizenegger, Michael Gmachl, Dorothea Rudolph, Christopher P. Vellano, Marcelo Marotti, Vitomir Vucenovic, Timothy P. Heffernan, Joseph R. Marszalek, Mark P. Petronczki, Norbert Kraut
Meeting Abstract
Oncology
Huaixiang Hao, Chen Liu, Hongyun Wang, Hengyu Lu, Scott Delach, Matthew LaMarche, Jeffrey Engelman, Peter Hammerman, Giordano Caponigro, Susan Moody, Morvarid Mohseni
Meeting Abstract
Oncology
Hengyu Lu, Chen Liu, Roberto Velazquez, Hongyun Wang, Lukas M. Dunkl, Malika Kazic-Legueux, Anne Haberkorn, Eric Billy, Eusebio Manchado, Saskia M. Brachmann, Susan Moody, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro, Morvarid Mohseni, Huai-Xiang Hao
MOLECULAR CANCER RESEARCH
(2020)
Meeting Abstract
Oncology
Hengyu Lu, Chen Liu, Roberto Velazquez, Hongyun Wang, Lukas M. Dunkl, Malika Kazic-Legueux, Anne Haberkorn, Eric Billy, Eusebio Manchado, Saskia M. Brachmann, Susan Moody, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro, Morvarid Mohseni, Huaixiang Hao
Meeting Abstract
Oncology
Huaixiang Hao, Hengyu Lu, Chen Liu, Matthew LaMarche, Jeffrey A. Engelman, Peter S. Hammerman, Giordano Caponigro