Review
Biochemistry & Molecular Biology
Wenjing Chen, Jong-In Park
Summary: BRAF mutation occurs in approximately 50% of tumors and targeting BRAF and MEK1/2 is a key therapeutic strategy. However, challenges remain in terms of tumor adaptation and resistance to treatment, necessitating the identification of resistance mechanisms and improvement of therapeutic approaches.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Weijia Cai, Mai Q. Nguyen, Nicole A. Wilski, Timothy J. Purwin, Megane Vernon, Manoela Tiago, Andrew E. Aplin
Summary: In this study, it was demonstrated that loss of phosphoinositide-dependent kinase-1 (PDPK1) enhances the efficacy of MEKi, and the synergistic effects of PDPK1 loss and MEKi were validated in NRAS mutant melanoma cell lines.
Article
Chemistry, Medicinal
Ramulu Poddutoori, Kimberly Aardalen, Kiran Aithal, Sanjeev Surendranath Barahagar, Charamanna Belliappa, Mark Bock, Shekar Chelur, Andrea Gerken, Sreevalsam Gopinath, Bjoern Gruenenfelder, Michael Kiffe, Maithreyi Krishnaswami, John Langowski, Sudharshan Madapa, Kishore Narayanan, Chetan Pandit, Sunil Kumar Panigrahi, Mark Perrone, Ravi Kumar Potakamuri, Murali Ramachandra, Anuradha Ramanathan, Rita Ramos, Emine Sager, Susanta Samajdar, Hosahalli S. Subramanya, Devaraja Seethappa Thimmasandra, Eleni Venetsanakos, Henrik Mobitz
Summary: This study reports the discovery of a novel MEK1/2 inhibitor that shows efficacy in both wildtype and mutant MEK1/2 models. The compound was optimized to address its liabilities and showed comparable efficacy to clinical MEK1/2 inhibitors in BRAF-mutant models.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Faiz Bilal, Enrique J. Arenas, Kim Pedersen, Alex Martinez-Sabadell, Behnam Nabet, Elizabeth Guruceaga, Silvestre Vicent, Josep Tabernero, Teresa Macarulla, Joaquin Arribas
Summary: This study demonstrates that SLUG confers resistance to MEK1/2 inhibitors in pancreatic cancer by uncoupling tumor progression from KRAS-RAF-MEK1/2-ERK1/2 signaling, providing new therapeutic opportunities.
Article
Oncology
J. Sastre, P. Garcia-Alfonso, J. M. Vieitez, M. T. Cano, F. Rivera, J. J. Reina-Zoilo, A. Salud-Salvia, G. Quintero, L. Robles-Diaz, M. J. Safont, A. La Casta, S. Gil, E. Polo, E. Asensio-Martinez, B. Garcia-Paredes, R. L. Lopez, M. Guillot, M. Valladares-Ayerbes, E. Aranda, E. Diaz-Rubio
Summary: The mutational status of BRAF and PIK3CA influences the outcomes of patients with RAS wild-type metastatic colorectal cancer, but does not appear to be helpful in selecting first-line targeted therapy. The efficacy of bevacizumab or cetuximab plus FOLFIRI was similar in both BRAF/PIK3CA wild-type and mutated tumors. Adverse events were comparable between the two treatment groups.
Article
Biochemistry & Molecular Biology
Michael Grasso, Gavin J. Bond, Ye-Jin Kim, Stefanie Boyd, Maria Matson Dzebo, Sebastian Valenzuela, Tiffany Tsang, Natalie A. Schibrowsky, Katherine B. Alwan, Ninian J. Blackburn, George M. Burslem, Pernilla Wittung-Stafshede, Duane D. Winkler, Ronen Marmorstein, Donita C. Brady
Summary: Studies show that copper (Cu) serves as an intracellular signaling mediator by connecting to the amplitude of mitogen-activated protein kinase signaling through direct interaction with kinases MEK1 and MEK2, influencing cell proliferation. The Cu chaperone CCS provides fidelity within a complex biological system, facilitating appropriate installation of Cu within the MEK1 kinase active site to modulate kinase activity.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Penglei Wang, Xuechao Jia, Bingbing Lu, Han Huang, Jialin Liu, Xuejiao Liu, Qiong Wu, Yamei Hu, Pan Li, Huifang Wei, Tingting Liu, Dengyun Zhao, Lingwei Zhang, Xueli Tian, Yanan Jiang, Yan Qiao, Wenna Nie, Xinli Ma, Ruihua Bai, Cong Peng, Zigang Dong, Kangdong Liu
Summary: In this study, Erianin was found to suppress the activation of the MAPK signaling pathway induced by BRAF V600E or RAS mutations in melanoma and colorectal cancer cells. It inhibited the activities of MEK1/2 and CRAF kinases, leading to the suppression of tumor growth. This discovery provides a promising candidate compound for the treatment of BRAF V600E or RAS mutant melanoma and colorectal cancer.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2023)
Article
Oncology
Jian Zhang, Jiaojiao Zhang, Wenli Liu, Rui Ge, Tianyuan Gao, Qiong Tian, Xin Mu, Lingyu Zhao, Xu Li
Summary: UBTF is a DNA binding protein involved in basal transcription and has been found to play a role in carcinogenesis in some cancers. In melanoma, UBTF was found to promote cell proliferation and cell cycle progression by upregulating GIT1 expression, thereby activating the MEK1/2-ERK1/2 signaling pathways. This study suggests that UBTF may be a potential therapeutic target for melanoma treatment.
CANCER CELL INTERNATIONAL
(2021)
Article
Food Science & Technology
Javier Moral-Sanz, Manuel A. Fernandez-Rojo, Jeremy Potriquet, Pamela Mukhopadhyay, Andreas Brust, Patrick Wilhelm, Taylor B. Smallwood, Richard J. Clark, Bryan G. Fry, Paul F. Alewood, Nicola Waddell, John J. Miles, Jason P. Mulvenna, Maria P. Ikonomopoulou
Summary: The Octopus Kaurna-derived peptide Octpep-1 was found to target the PI3K/AKT/mTOR signaling in human BRAF(V600E) melanoma cells, enhancing cytotoxicity when combined with rapamycin or LY3214996 inhibitors. Octpep-1-treated cells displayed reduced glycolysis and mitochondrial respiration, suggesting its potential as an optimal candidate for combination therapies against BRAF(V600E) mutations in melanoma.
Article
Cell Biology
Joe Taylor, Sarah Wilmore, Sophie Marriot, Karly-Rai Rogers-Broadway, Rachel Fell, Annabel R. Minton, Tom Branch, Meg Ashton-Key, Mark Coldwell, Freda K. Stevenson, Francesco Forconi, Andrew J. Steele, Graham Packham, Alison Yeomans
Summary: This study provides new insights into the regulation of mRNA translation in B-cell malignancies, highlighting the importance of combining kinase inhibitors to target translation control and MYC expression.
CELLULAR SIGNALLING
(2022)
Article
Oncology
Laurence Booth, Cameron West, Daniel Von Hoff, John M. Kirkwood, Paul Dent
Summary: The study revealed a lethal interaction between GZ17-6.02 and the MEK1/2 inhibitor trametinib and the B-RAF inhibitor dabrafenib, showing potential in killing melanoma cells and impacting multiple signaling pathways differently.
FRONTIERS IN ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Vlad-Adrian Afrasanie, Mihai-Vasile Marinca, Bogdan Gafton, Teodora Alexa-Stratulat, Alexandra Rusu, Eliza-Maria Froicu, Daniel Sur, Cristian Virgil Lungulescu, Larisa Popovici, Andrei-Vlad Lefter, Irina Afrasanie, Anca-Viorica Ivanov, Lucian Miron, Cristina Rusu
Summary: In this study, the frequency, distribution, coexistence, and clinicopathological and molecular correlations of RAS, BRAF, PIK3CA, and TP53 mutations were investigated in 104 patients with metastatic colorectal cancer from Northeastern Romania. TP53 was the most frequently mutated gene (73.1%), followed by KRAS (45.2%) and PIK3CA (6.7%). The study provides novel insights into genetic variations specific to the population from Northeastern Romania and enables the development of genetic profiles in a developing country with limited access to specialized genetic tests.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Zhiyang Zhou, Bi Peng, Juanni Li, Kewa Gao, Yuan Cai, Zhijie Xu, Yuanliang Yan
Summary: Alterations in MEK1 vary among different types of cancer, with distinct clinical implications on patient prognosis. This study provides a comprehensive analysis of MEK1 alterations and clinical significance, highlighting the importance of personalized therapy strategies based on MEK1 status in cancer treatment.
SCIENTIFIC REPORTS
(2021)
Article
Oncology
Khanh B. Tran, Gregory Gimenez, Peter Tsai, Sharada Kolekar, Euan J. Rodger, Aniruddha Chatterjee, Anower Jabed, Jen-Hsing Shih, Wayne R. Joseph, Elaine S. Marshall, Qian Wang, Cristin G. Print, Michael R. Eccles, Bruce C. Baguley, Peter R. Shepherd
Summary: The study characterizes a panel of cell lines from metastatic melanomas, identifying four subgroups of cell lines based on gene expression profiles and detecting HLA haplotypes and neoantigens in the lines through immunogenotyping. The NZM panel serves as a valuable resource for understanding the diversity of melanoma biology and the responses of melanoma to therapeutic interventions.
PIGMENT CELL & MELANOMA RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Ahlem Jebali, Maxime Battistella, Celeste Lebbe, Nicolas Dumaz
Summary: The network involving PI3K, AKT, and mTOR is important in melanoma oncogenesis, with RICTOR overexpression associated with poor prognosis. RICTOR enhances melanoma-initiating cells with stemness properties and contributes to resistance to BRAF inhibitors. An interaction between RICTOR and STAT3 in resistant cells, as well as a connection between RAS and RICTOR in resistant melanoma, were identified, suggesting RICTOR as a valuable therapeutic target in melanoma.
Article
Oncology
Roch-Philippe Charles, Gioia Iezza, Elena Amendola, David Dankort, Martin McMahon
Article
Oncology
Christy L. Trejo, Joseph Juan, Silvestre Vicent, Alejandro Sweet-Cordero, Martin McMahon
Article
Oncology
Christy L. Trejo, Shon Green, Victoria Marsh, Eric A. Collisson, Gioia Iezza, Wayne A. Phillips, Martin McMahon
Article
Developmental Biology
An-Chi Tien, Hui-Hsin Tsai, Anna V. Molofsky, Martin McMahon, Lynette C. Foo, Aparna Kaul, Joseph D. Dougherty, Nathaniel Heintz, David H. Gutmann, Ben A. Barres, David H. Rowitch
Article
Developmental Biology
Chun-Ying Li, Wanghee Cha, Hans-Ulrich Luder, Roch-Philippe Charles, Martin McMahon, Thimios A. Mitsiadis, Ophir D. Klein
DEVELOPMENTAL BIOLOGY
(2012)
Article
Medicine, Research & Experimental
Victoria Marsh Durban, Marian M. Deuker, Marcus W. Bosenberg, Wayne Phillips, Martin McMahon
JOURNAL OF CLINICAL INVESTIGATION
(2013)
Article
Oncology
Stephan Gysin, Jesse Paquette, Martin McMahon
MOLECULAR CANCER RESEARCH
(2012)
Editorial Material
Oncology
Martin McMahon
PIGMENT CELL & MELANOMA RESEARCH
(2011)
Article
Multidisciplinary Sciences
Emmanuelle Huillard, Rintaro Hashizume, Joanna J. Phillips, Amelie Griveau, Rebecca A. Ihrie, Yasuyuki Aoki, Theodore Nicolaides, Arie Perry, Todd Waldman, Martin McMahon, William A. Weiss, Claudia Petritsch, C. David James, David H. Rowitch
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2012)
Article
Multidisciplinary Sciences
Nan Tang, Wallace F. Marshall, Martin McMahon, Ross J. Metzger, Gail R. Martin
Article
Oncology
Eric A. Collisson, Christy L. Trejo, Jillian M. Silva, Shenda Gu, James E. Korkola, Laura M. Heiser, Roch-Philippe Charles, Brian A. Rabinovich, Byron Hann, David Dankort, Paul T. Spellman, Wayne A. Phillips, Joe W. Gray, Martin McMahon
Article
Oncology
Anne M. Strohecker, Jessie Yanxiang Guo, Gizem Karsli-Uzunbas, Sandy M. Price, Guanghua Jim Chen, Robin Mathew, Martin McMahon, Eileen White
Letter
Oncology
Gennie L. Parkman, David A. Kircher, Christopher M. Stehn, Martin McMahon, Sheri L. Holmen
PIGMENT CELL & MELANOMA RESEARCH
(2021)
Review
Dermatology
Gennie L. Parkman, Mona Foth, David A. Kircher, Sheri L. Holmen, Martin McMahon
Summary: Phosphatidylinositol-3'-kinases (PI3Ks) are a family of lipid kinases that regulate various biological processes by phosphorylating inositol ring of phosphatidylinositides. Activation of PI3K leads to accumulation of PI3K-lipids, which play important roles in cell growth, death, and metabolism. In cancers, aberrant activation of PI3K pathway cooperates with other protein kinases to promote tumor progression and metastasis.
EXPERIMENTAL DERMATOLOGY
(2022)