Review
Biochemistry & Molecular Biology
Yu-Chieh Su, Wei-Chang Lee, Chih-Chun Wang, Shyh-An Yeh, Wen-Hui Chen, Po-Jen Chen
Summary: This review discusses the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC radiotherapy resistance and highlights the therapeutic potential of small molecule inhibitors against this pathway for radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting the PI3K/AKT/mTOR signaling pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biology
Francisco Aguayo, Francisco Perez-Dominguez, Julio C. Osorio, Carolina Oliva, Gloria M. Calaf
Summary: High-risk human papillomaviruses (HR-HPVs) are responsible for cervical, anogenital and a subset of head and neck carcinomas (HNCs). Oropharyngeal cancers, a specific clinical entity, are highly associated with HR-HPV infections. HR-HPV's oncogenic mechanism involves the overexpression of E6/E7 oncoproteins, which downregulate p53 and pRB tumor suppressor proteins and affect the PI3K/AKT/mTOR signaling pathway. This review focuses on the relationship between HR-HPV and PI3K/AKT/mTOR signaling pathway activation in HNC, highlighting its therapeutic importance.
Review
Oncology
Soudeh Ghafouri-Fard, Ali Noie Alamdari, Yashar Noee Alamdari, Atefe Abak, Bashdar Mahmud Hussen, Mohammad Taheri, Elena Jamali
Summary: This review summarizes the crucial role of the PI3K/AKT pathway in the development of squamous cell carcinomas, its impact on patient survival, the effectiveness of targeted therapies against this pathway, and the potential diagnostic markers for different types of SCCs.
CANCER CELL INTERNATIONAL
(2022)
Article
Pharmacology & Pharmacy
Xingxing Hu, Menglin Zou, Lan Ni, Mingyang Zhang, Weishuai Zheng, Bing Liu, Zhenshun Cheng
Summary: DEC1 plays a significant role in pulmonary fibrosis by promoting epithelial-mesenchymal transition (EMT) through the PI3K/AKT/GSK-3 beta/beta-catenin integrated signaling pathway, leading to the accumulation of fibroblasts and myofibroblasts and excessive collagen deposition. Targeting DEC1 may be a potential novel therapeutic approach for idiopathic pulmonary fibrosis (IPF).
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Oncology
Ofra Novoplansky, Avital B. Shnerb, Divyasree Marripati, Sankar Jagadeeshan, Raghda Abu Shareb, Cristina Conde-Lopez, Jonathan Zorea, Manu Prasad, Talal Ben Lulu, Ksenia M. Yegodayev, Chen Benafsha, Yushi Li, Dexin Kong, Fengshen Kuo, Luc G. T. Morris, Ina Kurth, Jochen Hess, Moshe Elkabets
Summary: Blocking the MAPK pathway with trametinib has shown promise in HNSCC patients. However, trametinib treatment leads to overexpression and activation of EGFR, which reduces its efficacy. The study demonstrates that blocking the EGFR/PI3K pathway is necessary to improve trametinib efficacy in HNSCC.
MOLECULAR ONCOLOGY
(2023)
Article
Oncology
Xiao Ma, Hong Zhang, Qian Li, Erik Schiferle, Yao Qin, Suifang Xiao, Tiancheng Li
Summary: The study identified that FOXM1 promotes the expression of Linc-ROR, leading to activation of the LMO4-dependent AKT/PI3K signaling pathway which facilitates the occurrence and development of HNSCC.
FRONTIERS IN ONCOLOGY
(2021)
Article
Immunology
Yingjie Zhu, Dong Sun, Han Liu, Linzi Sun, Jing Jie, Jingjing Luo, Liping Peng, Lei Song
Summary: Bixin, a natural compound isolated from Bixa Orellana seeds, has shown potential in treating asthma by suppressing allergic airway inflammation, reversing glucocorticoids resistance, and alleviating airway remodeling and hyperresponsiveness. It functions as an antagonist of PI3K/Akt signaling, offering a novel strategy for asthma treatment.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Yaxuan Hou, Meng Zhou, Yuncheng Li, Tingting Tian, Xun Sun, Mo Chen, Wenmao Xu, Meixia Lu
Summary: Long noncoding RNAs (lncRNAs) play a role in the tumorigenesis of various tumors, but there is insufficient research on their association with the risk of head and neck squamous cell carcinoma (HNSCC). This study found that two SNPs (rs16854802 A > G and rs3113503 G > C) in LINC01614 increased the risk of HNSCC and disrupted the binding between LINC01614 and miRNA-616-3p, leading to increased expression of LINC01614. Additionally, upregulated LINC01614 was associated with poor prognosis in HNSCC patients, and knocking down LINC01614 inhibited the proliferation, invasion, and migration of HNSCC cells.
MOLECULAR CARCINOGENESIS
(2022)
Review
Oncology
Adriana Castelo de Moura, Daniele Xavier Assad, Juliana Amorim dos Santos, Isabela Porto de Toledo, Gustavo Barcelos Barra, Rogerio Moraes Castilho, Cristiane Helena Squarize, Eliete Neves Silva Guerra
Summary: The systematic review and meta-analysis examined the prevalence of PI3K-AKT-mTOR pathway mutations in head and neck cancer patients, identifying significant associations with advanced TNM stage and oropharyngeal HPV-positive tumors. Different mutation rates were found for genes like PIK3CA and PTEN, showing relevance to tumor characteristics and risk factors. The study suggests that these mutations could serve as potential prognostic factors and may guide future therapeutic targeting in HNC patients.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2021)
Article
Oncology
Dan Yu, Zhenlong Xiao, Zhefei Zou, Ling Lin, Jing Li, Jian Tan, Wei Chen
Summary: This study reveals the oncogenic role of IGF2BP2 and provides insights into its potential mechanism in HNSCC tumorigenesis. Additionally, IGF2BP2 might represent a promising therapeutic target and serve as a prognostic biomarker in patients with HNSCC.
FRONTIERS IN ONCOLOGY
(2023)
Article
Cell Biology
Taotao Hu, Fang Chen, Dan Chen, Hongqing Liang
Summary: In this study, the relationship between PTEN methylation and renal fibrosis was investigated. It was found that PTEN promoter region was methylated in a mouse model of unilateral ureteral obstruction (UUO), and the expression of PTEN was significantly reduced in the UUO group. Furthermore, DNMT3a negatively regulated PTEN to activate the PI3K/AKT signaling pathway and induce EMT in renal tubular epithelial cells, aggravating renal fibrosis.
CELLULAR SIGNALLING
(2022)
Editorial Material
Oncology
Hannah Zaryouh, Jinthe Van Loenhout, Marc Peeters, Jan Baptist Vermorken, Filip Lardon, An Wouters
Summary: Resistance to EGFR-targeted therapy in head and neck cancers is partially mediated by aberrant signaling of the PI3K/Akt pathway. Further research is needed to explore the potential of therapy-induced autophagy as an anti-tumor mechanism and to develop novel therapeutic strategies targeting both the EGFR and PI3K/Akt pathway.
Article
Genetics & Heredity
Lian Zheng, Zhenjie Guan, Miaomiao Xue
Summary: The study established a gene signature model based on the TGF-beta pathway, which has good predictive efficiency for predicting the prognosis of HNSCC patients and guiding the selection of immunotherapy. This model can help identify high-risk and low-risk patients and provide a new direction for research in individualized immuno-oncology.
FRONTIERS IN GENETICS
(2022)
Article
Oncology
Jin-Xing Hu, Ze-Qi Zheng, Ting Kang, Wei Qian, Shan-Hua Huang, Bin-Gong Li
Summary: The long noncoding RNA LINC00961 plays a crucial role in cancer and cardiovascular diseases. This study found that LINC00961 is involved in endothelial-mesenchymal transition induced by transforming growth factor beta and regulates cell injury and EndMT through the PTEN-PI3K-AKT pathway.
MOLECULAR MEDICINE REPORTS
(2022)
Article
Medicine, Research & Experimental
Liangmei Chen, Xiaofan Li, Yiyao Deng, Jianwen Chen, Mengjie Huang, Fengge Zhu, Zhumei Gao, Lingling Wu, Quan Hong, Zhe Feng, Guangyan Cai, Xuefeng Sun, Xueyuan Bai, Xiangmei Chen
Summary: This study found that the transformation of cells into myofibroblasts during renal injury is a common phenomenon and the process is associated with cellular respiration, regulated by TGF-beta 1. By inhibiting the production of cellular respiration, the occurrence of cell transformation can be slowed down.
JOURNAL OF TRANSLATIONAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Sumit J. Bandekar, Chun-Liang Chen, Sandeep K. Ravala, Jennifer N. Cash, Larisa V. Avramova, Mariya V. Zhalnina, J. Silvio Gutkind, Sheng Li, John J. G. Tesmer
Summary: The Trio scaffold contains two GEF modules selective for Rac and RhoA GTPases, with the C-terminal region enhancing Rac1 GEF activity. Characterization of accessory Trio domains may provide alternate routes for developing therapeutics to inhibit Trio activity in human cancer.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Dina Hingorani, Michael M. Allevato, Maria F. Camargo, Jacqueline Lesperance, Maryam A. Quraishi, Joseph Aguilera, Ida Franiak-Pietryga, Daniel J. Scanderbeg, Zhiyong Wang, Alfredo A. Molinolo, Diego Alvarado, Andrew B. Sharabi, Jack D. Bui, Ezra E. W. Cohen, Stephen R. Adams, J. Silvio Gutkind, Sunil J. Advani
Summary: The authors show that the combination of monomethyl auristatin and radiotherapy can promote anti-tumor immune responses and improve the response to checkpoint inhibitors in cancer therapy. This trimodal precision cytotoxic chemo-radio-immunotherapy paradigm has the potential to improve tumor control and patient outcomes.
NATURE COMMUNICATIONS
(2022)
Review
Oncology
Robert Saddawi-Konefka, Shiruyeh Schokrpur, Asona J. Lui, J. Silvio Gutkind
Summary: Research has shown that abnormalities in the ErbB signaling pathways play a crucial role in oncogenesis, and efforts to target these aberrations offer great potential in treating various types of cancer. While the focus has primarily been on the EGFR pathway, recent studies have identified significant dysregulation in the HER2 and HER3 signaling pathways in head and neck cancer. This review highlights clinical efforts to target these receptors and their aberrant signaling, including the use of small molecule inhibitors and blocking antibodies, in the treatment of head and neck squamous cell carcinomas and other malignancies.
Article
Oncology
Kris C. Wood, J. Silvio Gutkind
Article
Oncology
Cherie-Ann O. Nathan, D. Neil Hayes, Theodore Karrison, Olivier Harismendy, Jose M. Flores, Tara Moore-Medlin, Everett E. Vokes, J. Silvio Gutkind, Prakash Neupane, Glenn Mills, Zoukaa Sargi, Tanguy Seiwert, Juneko Grilley-Olson, Terry Day, Maura Gillison, James L. Wade, Lawrence Feldman, Gautam Jha, Mark Kozloff, Miriam O'Leary, Francis P. Worden, Ezra E. W. Cohen
Summary: This study aimed to investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival in advanced-stage HNSCC patients and to explore outcomes related to disease control-associated biological factors. The results suggest that p16-negative and TP53-mutated patients may benefit from adjuvant treatment with everolimus.
CLINICAL CANCER RESEARCH
(2022)
Review
Health Care Sciences & Services
Toshinori Ando, Kento Okamoto, Tomoaki Shintani, Souichi Yanamoto, Mutsumi Miyauchi, J. Silvio Gutkind, Mikihito Kajiya
Summary: Genetic alterations and dysregulation of signaling pathways are crucial for the development of cancer. Precision medicine allows for the selection of appropriate treatments based on genetic variations. Various genetic alterations in HNSCC disrupt the Hippo pathway and lead to hyperactivation of YAP/TAZ.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Biochemistry & Molecular Biology
Nadia Arang, Simone Lubrano, Damiano Cosimo Rigiracciolo, Daniela Nachmanson, Scott M. Lippman, Prashant Mali, Olivier Harismendy, J. Silvio Gutkind
Summary: G proteins and G protein-coupled receptors activate signal transduction pathways that promote cell growth and survival. This study found that G alpha q promotes PI3K/AKT signaling pathway activation, leading to resistance to FAK inhibition. These findings establish a novel link between G alpha q-driven signaling and the stimulation of PI3K, demonstrating the aberrant activation of signaling networks underlying the growth and survival of UM and other G alpha q-driven malignancies.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Oncology
Alison E. Smith, Stacia Chan, Zhiyong Wang, Asako Mccloskey, Quinn Reilly, Jayden Z. Wang, Hetika Vora Patel, Keiichi Koshizuka, Harris S. Soifer, Linda Kessler, Ashley Dayoub, Victoria Villaflor, Douglas R. Adkins, Justine Y. Bruce, Alan L. Ho, Cesar A. Perez, Glenn J. Hanna, Amaya Gasco Hernandez, Andrew Saunders, Stephen Dale, J. Silvio Gutkind, Francis Burrows, Shivani Malik
Summary: The outcomes for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) are poor, and there are limited treatment options for those who progress on standard-of-care immunotherapy. Researchers have developed a combination therapy targeting the key drivers of HNSCC, PI3K-mTOR and HRAS, using the inhibitors tipifarnib and alpelisib. This combination therapy has shown promise in preclinical studies and early clinical trials, with potential to benefit over 45% of patients with recurrent/metastatic HNSCC. Additionally, tipifarnib may enhance the effectiveness of other targeted therapies by preventing adaptive resistance.
Article
Oncology
Sankar Jagadeeshan, Manu Prasad, Mai Badarni, Talal Ben-Lulu, Vijayasteltar Belsamma Liju, Sooraj Mathukkada, Claire Saunders, Avital Beeri Shnerb, Jonathan Zorea, Ksenia M. Yegodayev, Monica Wainer, Liza Vtorov, Irit Allon, Ofir Cohen, Gro Gausdal, Dinorah Friedmann-Morvinski, Sok Ching Cheong, Alan L. Ho, Ari J. Rosenberg, Linda Kessler, Francis Burrows, Dexin Kong, Jennifer R. Grandis, J. Silvio Gutkind, Moshe Elkabets
Summary: The presence of mutated HRAS in head and neck cancer patients is associated with poor prognosis and high metastasis rate. Mutated HRAS promotes cancer cell invasion and metastasis by suppressing the Hippo pathway and promoting AXL expression. The use of tipifarnib, a farnesyltransferase inhibitor, can activate the Hippo pathway, suppress metastasis, and regulate angiogenesis in HNC.
Article
Biotechnology & Applied Microbiology
Shuo Wang, Zhi-Zhong Wu, Su-Wen Zhu, Shu-Cheng Wan, Meng-Jie Zhang, Bo-Xin Zhang, Qi-Chao Yang, Yao Xiao, Hao Li, Liang Mao, Zhi-Yong Wang, J. Silvio Gutkind, Zhi-Jun Sun
Summary: Immune checkpoint blockade (ICB) treatment is effective in oncology, but has limitations including low response rates and a lack of efficacy predictors. Gasdermin protein expression is associated with a favorable tumor immune microenvironment and prognosis in head and neck squamous cell carcinoma. CTLA-4 blockade treatment induces gasdermin-mediated pyroptosis of tumor cells, with gasdermin expression correlating with treatment effectiveness. CTLA-4 blockade activates CD8+ T cells and increases levels of IFN-g and TNF-a cytokines, triggering tumor cell pyroptosis and release of inflammatory substances and chemokines.
Article
Immunology
Victoria H. Wu, Bryan S. Yung, Farhoud Faraji, Robert Saddawi-Konefka, Zhiyong Wang, Alexander T. Wenzel, Miranda J. Song, Meghana S. Pagadala, Lauren M. Clubb, Joshua Chiou, Sanju Sinha, Marin Matic, Francesco Raimondi, Thomas S. Hoang, Rebecca Berdeaux, Dario A. A. Vignali, Ramiro Iglesias-Bartolome, Hannah Carter, Eytan Ruppin, Jill P. Mesirov, J. Silvio Gutkind
Summary: The authors used computational screening and chemogenetic analysis of transgenic mice to show that G alpha(s)-coupled G-protein-coupled receptors (GPCRs) on exhausted CD8(+) T cells play a role in suppressing effector functions and inhibiting the protective effects of immune checkpoint immunotherapy. They found an enrichment of G alpha(s)-coupled GPCRs on exhausted CD8(+) T cells and identified several specific receptors that promote T cell dysfunction. By activating the G alpha(s) signaling axis, they demonstrated that CD8(+) T cell dysfunction and immunotherapy failure can be promoted. These findings suggest that G alpha(s)-GPCRs could be targeted to enhance the response to immune checkpoint blockade immunotherapies.
Article
Biochemistry & Molecular Biology
Natalie Hewitt, Ning Ma, Nadia Arang, Sarah A. Martin, Ajit Prakash, Jeffrey F. DiBerto, Kevin M. Knight, Soumadwip Ghosh, Reid H. J. Olsen, Bryan L. Roth, J. Silvio Gutkind, Nagarajan Vaidehi, Sharon L. Campbell, Henrik G. Dohlman
Summary: Heterotrimeric guanine nucleotide-binding proteins (G proteins) act as molecular switches for cellular growth and metabolism. Mutations in the glutamine residue critical for GTP hydrolysis in the G protein alpha subunit are common in uveal melanoma. Our study reveals that these mutations have functional diversity and contribute to G protein functions beyond GTP hydrolysis.
Article
Multidisciplinary Sciences
Meghana Pagadala, Timothy J. Sears, Victoria H. Wu, Eva Perez-Guijarro, Hyo Kim, Andrea Castro, James V. Talwar, Cristian Gonzalez-Colin, Steven Cao, Benjamin J. Schmiedel, Shervin Goudarzi, Divya Kirani, Jessica Au, Tongwu Zhang, Teresa Landi, Rany M. Salem, Gerald P. Morris, Olivier Harismendy, Sandip Pravin Patel, Ludmil B. Alexandrov, Jill P. Mesirov, Maurizio Zanetti, Chi-Ping Day, Chun Chieh Fan, Wesley K. Thompson, Glenn Merlino, J. Silvio Gutkind, Pandurangan Vijayanand, Hannah Carter
Summary: Understanding how host genetics affects the tumor immune microenvironment (TIME) is essential for personalized cancer screening and treatment strategies. A study analyzed the eQTLs affecting TIME and found that they are enriched in areas of active transcription and associated with gene expression in specific immune cell subsets. Polygenic score models built with TIME eQTLs can stratify cancer risk, survival, and immune checkpoint blockade (ICB) response. Inhibiting the CTSS gene, which is implicated by the polygenic models, slows tumor growth and extends survival, suggesting the potential of integrating genetic factors and TIME characteristics for immunotherapy targets.
NATURE COMMUNICATIONS
(2023)
Article
Oncology
Ana Ruiz-Saenz, Chloe E. Atreya, Changjun Wang, Bo Pan, Courtney A. Dreyer, Diede Brunen, Anirudh Prahallad, Denise P. Munoz, Dana J. Ramms, Valeria Burghi, Danislav S. Spassov, Eleanor Fewings, Yeonjoo C. Hwang, Cynthia Cowdrey, Christina Moelders, Cecilia Schwarzer, Denise M. Wolf, Byron Hann, Scott R. VandenBerg, Kevan Shokat, Mark M. Moasser, Rene Bernards, J. Silvio Gutkind, Laura J. van 't Veer, Jean-Philippe Coppe
Summary: Coppe and colleagues discover a resistance mechanism in BRAF(V600E) colorectal cancers that can be overcome with COX2 inhibitors. SRC kinases play a role in resistance to BRAF/EGFR-targeted therapy and can be effectively targeted in combination with BRAF and EGFR. Compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E-2 loop, which can be blocked with COX2 inhibitors. Co-targeting COX2, BRAF, and EGFR promotes long-lasting suppression of tumor growth in patient-derived tumor xenograft models.
Article
Biochemistry & Molecular Biology
Valeria Burghi, Justine S. Paradis, Adam Officer, Sendi Rafael Adame-Garcia, Xingyu Wu, Edda S. F. Matthees, Benjamin Barsi-Rhyne, Dana J. Ramms, Lauren Clubb, Monica Acosta, Pablo Tamayo, Michel Bouvier, Asuka Inoue, Mark von Zastrow, Carsten Hoffmann, J. Silvio Gutkind
Summary: This study focuses on the role of beta-arrestins in G protein-coupled receptor (GPCR) signaling. It is found that while G proteins are essential for GPCR signaling, beta-arrestins play a more prominent role in signal compartmentalization and modulation of gene expression.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)