Article
Multidisciplinary Sciences
Shankar Dhamodharan, Mathew Maria Rose, Sundaram Reddy Chakkarappan, Karuppiah Vijayamuthuramalingam Umadharshini, Ramalingam Arulmurugan, Shanmugam Subbiah, Ituro Inoue, Arasambattu Kannan Munirajan
Summary: The genetic variant in EGFR-AS1 modulates the expression of EGFR-D and A isoforms, suggesting its potential role in patients with head and neck cancer.
SCIENTIFIC REPORTS
(2021)
Article
Medicine, Research & Experimental
Francesca Citron, Ilenia Segatto, Lorena Musco, Ilenia Pellarin, Gian Luca Rampioni Vinciguerra, Giovanni Franchin, Giuseppe Fanetti, Francesco Micciche, Vittorio Giacomarra, Valentina Lupato, Andrea Favero, Isabella Concina, Sanjana Srinivasan, Michele Avanzo, Isabella Castiglioni, Luigi Barzan, Sandro Sulfaro, Gianluigi Petrone, Andrea Viale, Giulio F. Draetta, Andrea Vecchione, Barbara Belletti, Gustavo Baldassarre
Summary: EGFR activation upregulates miR-9 expression, sustaining aggressiveness and resistance to RT+CTX in HNSCC. miR-9 may serve as a valuable biomarker for selecting HNSCC patients who may benefit from RT+CTX therapy.
EMBO MOLECULAR MEDICINE
(2021)
Article
Oncology
Carolin Selenz, Anik Compes, Marieke Nill, Sven Borchmann, Margarete Odenthal, Alexandra Florin, Johannes Braegelmann, Reinhard Buettner, Lydia Meder, Roland T. Ullrich
Summary: EGFR inhibition promotes immune cell infiltration in the tumour microenvironment and enhances response to immune checkpoint inhibitors in EGFR-driven lung cancer.
Article
Multidisciplinary Sciences
Jacqulyne P. Robichaux, Xiuning Le, R. S. K. Vijayan, J. Kevin Hicks, Simon Heeke, Yasir Y. Elamin, Heather Y. Lin, Hibiki Udagawa, Ferdinandos Skoulidis, Hai Tran, Susan Varghese, Junqin He, Fahao Zhang, Monique B. Nilsson, Lemei Hu, Alissa Poteete, Waree Rinsurongkawong, Xiaoshan Zhang, Chenghui Ren, Xiaoke Liu, Lingzhi Hong, Jianjun Zhang, Lixia Diao, Russell Madison, Alexa B. Schrock, Jennifer Saam, Victoria Raymond, Bingliang Fang, Jing Wang, Min Jin Ha, Jason B. Cross, Jhanelle E. Gray, John Heymach
Summary: The study characterized the mutational landscape in 16,715 patients with EGFR-mutant NSCLC and established the structure-function relationship of EGFR mutations on drug sensitivity. EGFR mutations can be separated into four distinct subgroups based on sensitivity and structural changes, predicting patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. This structure-based approach delineates functional groups of EGFR mutations that can effectively guide treatment choices and suggest potential improvement in prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
Article
Biochemistry & Molecular Biology
Youwei Lu, Fengying Wu, Qiuyi Cao, Yu Sun, Moli Huang, Jing Xiao, Bin Zhou, Liang Zhang
Summary: In lung adenocarcinoma (LUAD) patients with EGFR-activating mutations, decreases in CD8(+) TILs density and function, downregulation of PD-L1, and upregulation of B7-H4 were observed. B7-H4 may serve as an alternative immune-checkpoint molecule and a potential therapeutic target for LUAD with EGFR MT.
Article
Cell Biology
Sonali Bahl, Hongbo Ling, Nuwan P. N. Acharige, Irene Santos-Barriopedro, Mary Kay H. Pflum, Edward Seto
Summary: HDAC1 is a key enzyme involved in the removal of acetyl groups from proteins, impacting gene transcription and cell processes. Its functions and activities are regulated by post-translational modifications, with EGFR activity promoting tyrosine phosphorylation of HDAC1 to regulate its activity. This phosphorylation may offer a potential target for cancer treatment strategies aiming to manipulate HDAC1 levels.
CELL DEATH & DISEASE
(2021)
Article
Chemistry, Physical
Luca Bertini, Valeria Libera, Francesca Ripanti, Tilo Seydel, Marco Paolantoni, Andrea Orecchini, Caterina Petrillo, Lucia Comez, Alessandro Paciaroni
Summary: This study characterized the internal dynamics of Tel22 G4s using neutron scattering techniques, and found that the interaction with two ligands increased the overall mobility of Tel22 and decreased its stiffness. The complexation also resulted in more atomic groups participating in fast dynamics, along with an increase in relevant characteristic length scales. These findings may be crucial for understanding the complexation mechanisms.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)
Article
Multidisciplinary Sciences
Tyler S. Beyett, Ciric To, David E. Heppner, Jaimin K. Rana, Anna M. Schmoker, Jaebong Jang, Dries J. H. De Clercq, Gabriel Gomez, David A. Scott, Nathanael S. Gray, Pasi A. Janne, Michael J. Eck
Summary: This study investigates the molecular mechanisms and structural basis of drug resistance in lung cancer and the combination of allosteric and ATP-competitive inhibitors to overcome resistance. The findings highlight the importance of the P-loop in the synergy between allosteric inhibitors and EGFR variants.
NATURE COMMUNICATIONS
(2022)
Review
Chemistry, Medicinal
Jie He, Zhihui Zhou, Xin Sun, Zunhua Yang, Pengwu Zheng, Shan Xu, Wufu Zhu
Summary: Epidermal growth factor receptor (EGFR) is a crucial target for treating non-small cell lung cancer (NSCLC), with first to third-generation inhibitors showing efficacy but leading to resistance after 9-15 months. Major breakthroughs in understanding the resistance mechanisms of third-generation inhibitors are still lacking. The fourth-generation EGFR-TKIs show promise in overcoming resistance.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Shigeki Nanjo, Wei Wu, Niki Karachaliou, Collin M. Blakely, Junji Suzuki, Yu-Ting Chou, Siraj M. Ali, D. Lucas Kerr, Victor R. Olivas, Jonathan Shue, Julia Rotow, Manasi K. Mayekar, Franziska Haderk, Nilanjana Chatterjee, Anatoly Urisman, Jia Chi Yeo, Anders J. Skanderup, Aaron C. Tan, Wai Leong Tam, Oscar Arrieta, Kazuyoshi Hosomichi, Akihiro Nishiyama, Seiji Yano, Yuriy Kirichok, Daniel S. W. Tan, Rafael Rosell, Ross A. Okimoto, Trever G. Bivona
Summary: This study investigates the impact of co-occurring genetic alterations on mutant EGFR and identifies the deficiency of RNA-binding factor RBM10 as a factor that decreases the efficacy of EGFR inhibitors in lung cancer treatment. The study reveals that RBM10 modulates tumor cell apoptosis by regulating the alternative splicing of Bcl-x and its deficiency diminishes EGFR inhibitor-mediated apoptosis. The findings suggest that co-occurring genetic alterations and splicing factor deficiency play a role in determining the sensitivity to targeted kinase inhibitor therapy.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Oncology
Bo Kyung A. Seong, Neekesh Dharia, Shan Lin, Katherine A. Donovan, Shasha Chong, Amanda Robichaud, Amy Conway, Amanda Hamze, Linda Ross, Gabriela Alexe, Biniam Adane, Behnam Nabet, Fleur M. Ferguson, Bjorn Stolte, Emily Jue Wang, Jialin Sun, Xavier Darzacq, Federica Piccioni, Nathanael S. Gray, Eric S. Fischer, Kimberly Stegmaier
Summary: Fusion-transcription factors (fusion-TFs) are difficult to therapeutically target, but recent research has discovered TRIM8 as a selective E3 ubiquitin ligase for degrading a driver fusion-TF in Ewing sarcoma. Knocking out TRIM8 leads to increased levels of the fusion TF, EWS/FLI, providing a potential strategy for exploiting oncogene overdose in Ewing sarcoma and other fusion-TF driven cancers.
Article
Biochemistry & Molecular Biology
Steven Hughes, Jessica K. Edwards, Ashleigh G. Wilcox, Carina A. Pothecary, Alun R. Barnard, Russell Joynson, Greg Joynson, Mark W. Hankins, Stuart N. Peirson, Gareth Banks, Patrick M. Nolan
Summary: Mutations in the transcription factor ZFHX3 have been shown to affect circadian rhythms in mice, with further investigation revealing its impact on retinal function, particularly in altered light responses and increased sensitivity to pupillary reflexes.
Article
Chemistry, Medicinal
Hong-Yi Zhao, Hai-Peng Wang, Yu-Ze Mao, Hao Zhang, Minhang Xin, Xiao-Xiao Xi, Hao Lei, Shuai Mao, Dong-Hui Li, San-Qi Zhang
Summary: This study developed proteolysis targeting chimeras (PROTACs) targeting EGFR mutants by optimizing covalent EGFR ligands to overcome drug resistance in non-small-cell lung cancer (NSCLC). The covalent PROTAC CP17 was discovered to be a highly potent degrader against EGFRL858R/T790M and EGFRdel19 with excellent selectivity. Mechanism investigation showed that the lysosome was involved in the degradation process. Importantly, the covalent binding strategy was proven to be effective for designing PROTACs targeting EGFRL858R/T790M.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Takahiro Yoshizawa, Ken Uchibori, Mitsugu Araki, Shigeyuki Matsumoto, Biao Ma, Ryo Kanada, Yosuke Seto, Tomoko Oh-hara, Sumie Koike, Ryo Ariyasu, Satoru Kitazono, Hironori Ninomiya, Kengo Takeuchi, Noriko Yanagitani, Satoshi Takagi, Kazuma Kishi, Naoya Fujita, Yasushi Okuno, Makoto Nishio, Ryohei Katayama
Summary: This study focused on a lung cancer patient with an EGFR-L747P mutation, which was originally misidentified and resistant to certain EGFR-TKIs. Computational structural analysis was used to investigate the impact of the mutation on the active conformation.
NPJ PRECISION ONCOLOGY
(2021)
Article
Gastroenterology & Hepatology
Yun Beom Sang, Gwangil Kim, Sohyun Hwang, Haeyoun Kang, Hong Jae Chon
Summary: We report a case of a patient with c-MET amplified hepato-cellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to previous lines of systemic therapy, maintaining a partial response for over 9 months.
JOURNAL OF CLINICAL AND TRANSLATIONAL HEPATOLOGY
(2022)
Article
Cell Biology
Kaustav Das Gupta, Melanie R. Shakespear, James E. B. Curson, Ambika M. V. Murthy, Abishek Iyer, Mark P. Hodson, Divya Ramnath, Vikas A. Tillu, Jessica B. von Pein, Robert C. Reid, Kathryn Tunny, Daniel M. Hohenhaus, Shayli Varasteh Moradi, Gregory M. Kelly, Takumi Kobayashi, Jennifer H. Gunter, Alexander J. Stevenson, Weijun Xu, Lin Luo, Alun Jones, Wayne A. Johnston, Antje Blumenthal, Kirill Alexandrov, Brett M. Collins, Jennifer L. Stow, David P. Fairlie, Matthew J. Sweet
Article
Oncology
Melody Cheong, Kate H. Gartlan, Jason S. Lee, Siok-Keen Tey, Ping Zhang, Rachel D. Kuns, Christopher E. Andoniou, Jose Paulo Martins, Karshing Chang, Vivien R. Sutton, Greg Kelly, Antiopi Varelias, Slavica Vuckovic, Kate A. Markey, Glen M. Boyle, Mark J. Smyth, Christian R. Engwerda, Kelli P. A. MacDonald, Joseph A. Trapani, Mariapia A. Degli-Esposti, Motoko Koyama, Geoffrey R. Hill
CANCER IMMUNOLOGY RESEARCH
(2020)
Article
Genetics & Heredity
Rinal Sahputra, Emma A. Murphy, Ruth Forman, Iris Mair, Muhammad Z. H. Fadlullah, Ari Waisman, Werner Muller, Kathryn J. Else
JOURNAL OF MOLECULAR MEDICINE-JMM
(2020)
Article
Biology
Renaud Mevel, Ivana Steiner, Susan Mason, Laura C. A. Galbraith, Rahima Patel, Muhammad Z. H. Fadlullah, Imran Ahmad, Hing Y. Leung, Pedro Oliveira, Karen Blyth, Esther Baena, Georges Lacaud
Article
Oncology
Gregory M. Kelly, Fares Al-Ejeh, Robert McCuaig, Francesco Casciello, Nabilah Ahmad Kamal, Blake Ferguson, Antonia L. Pritchard, Sayed Ali, Ines P. Silva, James S. Wilmott, Georgina Long, Richard A. Scolyer, Sudha Rao, Nicholas K. Hayward, Frank Gannon, Jason S. Lee
Summary: The study suggests that LC3B may serve as a biomarker for checkpoint inhibitor blockade to guide patient selection. Additionally, G9a inhibition shows potential in enhancing the efficacy of checkpoint inhibitor blockade and increasing response rates in melanoma patients undergoing immunotherapy.
CLINICAL CANCER RESEARCH
(2021)
Review
Cell Biology
Wen Hao Neo, Michael Lie-A-Ling, Muhammad Zaki Hidayatullah Fadlullah, Georges Lacaud
Summary: During ontogeny, the establishment of the hematopoietic system occurs in different phases, from the yolk sac to the main arteries of the embryo. It has been discovered that yolk sac cells, initially thought to only bridge the gap to hematopoietic stem cells (HSCs), also play a role in embryonic organogenesis. Some of these cells persist into adulthood as distinct hematopoietic populations, opening up a new area of research.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Hematology
Muhammad Zaki Hidayatullah Fadlullah, Wen Hao Neo, Michael Lie-a-ling, Roshana Thambyrajah, Rahima Patel, Renaud Mevel, Irene Aksoy, Nam Do Khoa, Pierre Savatier, Laura Fontenille, Syed Murtuza Baker, Magnus Rattray, Valerie Kouskoff, Georges Lacaud
Summary: In vitro generation and expansion of hematopoietic stem cells hold great promise for treating diseases related to bone marrow or blood transplantation. The endothelial-to-hematopoietic transition process involves the angiotensin-I converting enzyme (ACE) expression and the involvement of AGM RUNX1(+) niche cells in supporting hematopoiesis.
Article
Oncology
Francesco Casciello, Gregory M. Kelly, Priya Ramarao-Milne, Nabilah Kamal, Teneale A. Stewart, Pamela Mukhopadhyay, Stephen H. Kazakoff, Mariska Miranda, Dorim Kim, Felicity M. Davis, Nicholas K. Hayward, Paula M. Vertino, Nicola Waddell, Frank Gannon, Jason S. Lee
Summary: G9a and EZH2, two histone methyltransferases commonly upregulated in several cancer types, cooperatively repress molecular pathways responsible for tumor cell death, and their simultaneous inhibition can induce tumor cell death.
Article
Multidisciplinary Sciences
Wen Hao Neo, Yiran Meng, Alba Rodriguez-Meira, Muhammad Z. H. Fadlullah, Christopher A. G. Booth, Emanuele Azzoni, Supat Thongjuea, Marella F. T. R. de Bruijn, Sten Eirik W. Jacobsen, Adam J. Mead, Georges Lacaud
Summary: The study reveals the crucial role of Ezh2 in modulating Wnt signaling during the generation of EMPs from YS HE. Loss of EZH2 activity in HE leads to the generation of non-functional EMPs due to a lack of Wnt signaling downregulation, while the generation of primitive erythroid cells is not affected. EZH2 is essential for the generation of functional EMPs at the onset of the endothelial-to-hematopoietic transition but becomes dispensable later on.
NATURE COMMUNICATIONS
(2021)
Article
Immunology
Chai Phei Gan, Bernard Kok Bang Lee, Shin Hin Lau, Thomas George Kallarakkal, Zuraiza Mohamad Zaini, Bryan Kit Weng Lye, Rosnah Binti Zain, Hans Prakash Sathasivam, Joe Poh Sheng Yeong, Natalia Savelyeva, Gareth Thomas, Christian H. Ottensmeier, Hany Ariffin, Sok Ching Cheong, Kue Peng Lim
Summary: Distinct immune responses are present in high-risk oral potentially malignant disorders (OPMD). Moderate and severe oral epithelial dysplasia (OED) exhibit high lymphocyte infiltration and upregulation of immune genes. Three subtypes of moderate and severe OED were identified: immune cytotoxic, non-cytotoxic, and non-immune reactive.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Nabil F. Saba, Conor E. Steuer, Asari Ekpenyong, Ashley McCook-Veal, Kelly Magliocca, Mihir Patel, Nicole C. Schmitt, William Stokes, James E. Bates, Soumon Rudra, Jill Remick, Mark McDonald, Marin Abousaud, Aik Choon Tan, Muhammad Zaki Hidayatullah Fadlullah, Ritu Chaudhary, Jameel Muzaffar, Kedar Kirtane, Yuan Liu, Georgia Z. Chen, Dong M. Shin, Yong Teng, Christine H. Chung
Summary: PD-1 therapy is standard treatment for recurrent metastatic head and neck squamous cell carcinoma. The combination of Pembrolizumab and Cabozantinib shows promising clinical activity. Further research is needed.
Article
Genetics & Heredity
Min Hu, Samuel Coleman, Muhammad Zaki Hidayatullah Fadlullah, Daniel Spakowicz, Christine H. Chung, Aik Choon Tan
Summary: Patients with human papillomavirus-negative head and neck squamous cell carcinoma (HPV-negative HNSCC) have worse outcomes than HPV-positive HNSCC. In our study, we found that microbial signatures can distinguish Hypoxia/Immune phenotypes similar to gene expression signatures in molecularly classified tumor groups. Additionally, we identified three highly-correlated microbes that are crucial for immunotherapy response in immune processes. The co-abundance of these three microbes significantly affects the survival of patients in a molecularly heterogenous group.
Correction
Biochemistry & Molecular Biology
Adrian P. Wiegmans, Ambber Ward, Ekaterina Ivanova, Pascal H. G. Duijf, Mark N. Adams, Idris Mohd Najib, Romy Van Oosterhout, Martin C. Sadowski, Greg Kelly, Scott W. Morrical, Ken O'Byrne, Jason S. Lee, Derek J. Richard
Article
Biochemistry & Molecular Biology
Adrian P. Wiegmans, Ambber Ward, Ekaterina Ivanova, Pascal H. G. Duijf, Mark N. Adams, Idris Mohd Najib, Romy Van Oosterhout, Martin C. Sadowski, Greg Kelly, Scott W. Morrical, Ken O'Byrne, Jason S. Lee, Derek J. Richard
Summary: Chemotherapy is commonly used for cancers with high levels of inherent genome instability, but may lead to chemotherapy resistance due to dysregulation of DNA repair pathways. This study revealed that genome instability in triple negative breast cancer can cause dysregulation of the non-homologous end joining pathway, leading to the emergence of chemotherapy resistance.
Article
Medicine, Research & Experimental
Francesco Casciello, Fares Al-Ejeh, Mariska Miranda, Greg Kelly, Eva Baxter, Karolina Windloch, Frank Gannon, Jason S. Lee