Article
Oncology
Oren Yakovian, Julia Sajman, Rand Arafeh, Yair Neve-Oz, Michal Alon, Yardena Samuels, Eilon Sherman
Summary: The study reveals the nanoscale organization and signal coupling of NRas and BRAF in melanoma cells, showing that mutant NRas exhibits more pronounced self-clustering and increased association with BRAF. The findings suggest a new regulatory mechanism for NRas signaling and potential therapeutic targets for MEK inhibitors in melanoma.
Article
Oncology
Hima Patel, Rosalin Mishra, Nour Yacoub, Samar Alanazi, Mary Kate Kilroy, Joan T. Garrett
Summary: Melanoma, accounting for only 4% of skin cancer, is a major cause of skin cancer related deaths. Resistance to FDA approved drugs dabrafenib and trametinib in treating BRAFV600E melanoma is mediated by the activation of IGF1R and IR. Combining dabrafenib and trametinib with IGF1R/IR inhibitor BMS-754807 effectively inhibits proliferation and tumor growth, offering potential treatment options for patients with BRAF-mutant melanoma.
Article
Biochemistry & Molecular Biology
Shujun Han, Mo Zhang, Xiaoyan Qu, Zihao Wu, Zongguan Huang, Yiming Hu, Ying Li, Lanlan Cui, Lu Si, Jiankang Liu, Yongping Shao
Summary: This study identifies a signaling pathway involving SOX10low/TGF-beta/LAMB3/FAK/MMPs that determines the migration and invasion properties of MAPKi-resistant melanoma cells. The LAMB3-Integrinα 3/α 6 signaling mediates the motile and invasive phenotype of resistant cells. SOX10 deficiency in MAPKi-resistant melanoma cells drives LAMB3 upregulation through TGF-beta signaling, and the pro-invasiveness effect of LAMB3 is mediated by the FAK/MMPs axis.
Article
Oncology
Shaheer Khan, Sapna P. Patel, Alexander N. Shoushtari, Grazia Ambrosini, Serge Cremers, Shing Lee, Lauren Franks, Shahnaz Singh-Kandah, Susana Hernandez, Naomi Sender, Kristina Vuolo, Alexandra Nesson, Prabhjot Mundi, Benjamin Izar, Gary K. Schwartz, Richard D. Carvajal
Summary: The study tested the intermittent dosing schedule of selumetinib in patients with metastatic uveal melanoma. The results showed an increased maximum tolerated dose but no significant clinical efficacy.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biotechnology & Applied Microbiology
Sathya Neelature Sriramareddy, Fernanda Faiao-Flores, Michael F. Emmons, Biswarup Saha, Srikumar Chellappan, Clayton Wyatt, Inna Smalley, Jonathan D. Licht, Michael A. Durante, J. William Harbour, Keiran S. M. Smalley
Summary: This study investigates the role of HDAC11 in uveal melanoma and finds that it plays a crucial role in therapy adaptation by modulating the YAP/TAZ signaling pathway, leading to the escape of MEKi therapy.
CANCER GENE THERAPY
(2022)
Article
Oncology
Tyler D. Hitchman, Gabriella Bayshtok, Emilie Ceraudo, Amanda R. Moore, Cindy Lee, Ruobing Jia, Naitao Wang, Mohini R. Pachai, Alexander N. Shoushtari, Jasmine H. Francis, Youxin Guan, Juliet Chen, Matthew T. Chang, Barry S. Taylor, Thomas P. Sakmar, Thomas Huber, Ping Chi, Yu Chen
Summary: The study found that the combination of Gα(q) and MEK inhibition showed promising therapeutic potential in treating melanoma, suggesting an improved therapeutic strategy for targeting Gα(q) in uveal melanoma.
CLINICAL CANCER RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Svenja Mergener, Jens T. Siveke, Samuel Pena-Llopis
Summary: The study found that monosomy of chromosome 3 (M3) and mutations in BAP1 are associated with higher resistance to MEK inhibitors in uveal melanoma. Reconstitution of BAP1 was unable to restore sensitivity to MEK inhibition. Comparison of UM tumors with mutations in BAP1 and wild-type BAP1 from TCGA showed clear differentiation in overall and progression-free survival.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Justine S. Paradis, Monica Acosta, Robert Saddawi-Konefka, Ayush Kishore, Frederico Gomes, Nadia Arang, Manoela Tiago, Silvia Coma, Simone Lubrano, Xingyu Wu, Kyle Ford, Chi-Ping Day, Glenn Merlino, Prashant Mali, Jonathan A. Pachter, Takami Sato, Andrew E. Aplin, J. Silvio Gutkind
Summary: Uveal melanoma is a common eye cancer with a high risk of developing metastatic uveal melanoma in the liver. The study has identified FAK and MEK-ERK co-targeting as a potential new precision therapeutic strategy for mUM, showing synergistic growth-inhibitory effects in vitro and in vivo models.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Pui-Kei Wu, Seung-Keun Hong, Jong-In Park
Summary: The study found that RNA interference of mortalin can induce cell death in vemurafenib-resistant B-Raf mutant melanoma cells, and chemical inhibition of MEK1/2 and ERK1/2 can suppress mortalin depletion-induced death. Therefore, mortalin may serve as a potential therapeutic target for BRAFi-resistant BRAF mutant tumors.
Article
Oncology
Renumathy Dhanasekaran, Aida S. Hansen, Jangho Park, Lea Lemaitre, Ian Lai, Nia Adeniji, Sibu Kuruvilla, Akanksha Suresh, Josephine Zhang, Varsha Swamy, Dean W. Felsher
Summary: MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. Overexpression of MYC increases immune-checkpoint expression, predicts nonresponsiveness to immune-checkpoint blockade, and is associated with Th2-like immune profile and reduced CD8 T-cell infiltration. MYC transcriptionally suppresses innate immunity and MHCI-mediated antigen presentation, impeding T-cell response. Combined blockade of PDL1 and CTLA4 can reverse MYC-driven immune suppression by recruiting proinflammatory antigen-presenting macrophages. Depletion of macrophages abrogates the antineoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma.
Article
Oncology
Masahiro Ohara, Kengo Saito, Ken Kageyama, Mizue Terai, Hanyin Cheng, Andrew E. Aplin, Takami Sato
Summary: Uveal melanoma (UM) is a common eye cancer in adults, with up to 50% of patients developing metastases. A preclinical study showed that combining CDK4/6 inhibitor with cMET inhibitor could provide significant clinical benefit to patients with metastatic uveal melanoma by suppressing tumor growth.
Article
Oncology
Anna Stagno, Sabrina Vari, Alessio Annovazzi, Vincenzo Anelli, Michelangelo Russillo, Francesco Cognetti, Virginia Ferraresi
Summary: This article reports the experience of rechallenging with BRAF and MEK inhibitors in patients with metastatic BRAF-mutated melanoma after progression with kinase inhibitors and immunotherapy. Two out of four patients had partial response, one patient had rapid disease progression, and another patient showed clinical benefit and stable disease. Adverse events were manageable and better tolerated at rechallenge by two patients.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Shumei Kato, Robert Porter, Ryosuke Okamura, Suzanna Lee, Ori Zelichov, Gabi Tarcic, Michael Vidne, Razelle Kurzrock
Summary: The study found that patients with tumors harboring RAS alterations with high MAPK activity had significantly longer median progression-free survival (PFS) and overall survival when treated with MEK inhibitors. This correlation between RAS-mutant cancers with greater MAPK signaling and PFS suggests potential clinical benefit of MEK inhibitor treatment.
EUROPEAN JOURNAL OF CANCER
(2021)
Editorial Material
Oncology
Sathya Neelature Sriramareddy, Keiran S. M. Smalley
Summary: Most uveal melanomas have mutations in G alpha q and show constitutive MAPK activation. While MEK inhibition has limited efficacy, combining G alpha q inhibitor with MEK inhibitor can lead to prolonged suppression of MAPK signaling and improved therapeutic responses in preclinical uveal melanoma models.
CLINICAL CANCER RESEARCH
(2021)
Article
Gastroenterology & Hepatology
Franck Carbonnel, Emilie Routier, Thierry Lazure, Charlotte Mussini, Christophe Bellanger, Carine Merklen, Bakhtiar Bejou, Anthony Buisson, Aurelien Amiot, Antoine Meyer, Catherine Dong, Caroline Robert
Summary: This study provides the first systematic description of colitis caused by dual blockade of BRAF and MEK kinases in the treatment of melanoma. The study found that severe colitis characterized by ulcerations of the right colon can occur, leading to symptoms such as diarrhea, rectal bleeding, abdominal pain, and intestinal obstruction. In some cases, the colitis was associated with ischemic changes and inflammation.
ALIMENTARY PHARMACOLOGY & THERAPEUTICS
(2023)