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Oncogene addiction

Leslie Duplaquet, Zoulika Kherrouche, Simon Baldacci, Philippe Jamme, Alexis B Cortot, Marie-Christine Copin, David Tulasne
Targeted therapies against receptor tyrosine kinases (RTKs) are currently used with success on a small proportion of patients displaying clear oncogene activation. Lung cancers with a mutated EGFR provide a good illustration. The efficacy of targeted treatments relies on oncogene addiction, a situation in which the growth or survival of the cancer cells depends on a single deregulated oncogene. MET, a member of the RTK family, is a promising target because it displays many deregulations in a broad panel of cancers...
March 19, 2018: Oncogene
Stephen Safe, James L Abbruzzese, Maen Abdelrahim, Erik Hedrick
Specificity protein (Sp) transcription factors (TFs) such as Sp1 are critical for early development but their expression decreases with age and there is evidence that transformation of normal cells to cancer cells is associated with upregulation of Sp1, Sp3 and Sp4 which are highly expressed in cancer cells and tumors. Sp1 is a negative prognostic factor for pancreatic, colon, glioma, gastric, breast, prostate, and lung cancer patients. Functional studies also demonstrate that Sp TFs regulate genes responsible for cancer cell growth, survival, migration/invasion, inflammation and drug resistance, and Sp1, Sp3 and Sp4 are also non-oncogene addiction (NOA) genes and important drug targets...
March 15, 2018: Cancer Prevention Research
Peiye Shen, Ying Jing, Ruiyun Zhang, Mei-Chun Cai, Pengfei Ma, Haige Chen, Guanglei Zhuang
Neuroendocrine bladder cancer is a relatively rare but often lethal malignancy, with cell of origin, oncogenomic architecture and standard treatment poorly defined. Here we performed comprehensive whole-genome and transcriptome sequencing on a unique cohort of genitourinary neuroendocrine neoplasms, mainly small cell carcinomas of the urinary bladder. The mutational landscape and signatures of neuroendocrine bladder cancer strikingly resembled those in conventional urothelial carcinoma, along with typically mixed histologies, supporting a common cellular origin...
March 14, 2018: Oncogene
Marcin D Tomala, Katarzyna Magiera-Mularz, Katarzyna Kubica, Sylwia Krzanik, Bartosz Zieba, Bogdan Musielak, Marcin Pustula, Grzegorz M Popowicz, Michael Sattler, Grzegorz Dubin, Lukasz Skalniak, Tad A Holak
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a...
March 5, 2018: European Journal of Medicinal Chemistry
Sabrina Rossi, Giovanna Finocchiaro, Silvia Marchetti, Luca Toschi, Armando Santoro
Despite efforts, brain metastases (BM) remain a critical issue in the management of patients affected by non-small-cell lung cancer (NSCLC). To date, radiotherapy is still considered the gold standard treatment; on the other hand, systemic chemotherapeutical agents are not so often an effective therapy for BM, whereas targeted agents in oncogene-addicted disease have shown a good activity also on BM. Anti-programmed death-1/programmed death ligand-1 agents represent a new valid therapeutic strategy for NSCLC as well as for several tumor types, but their efficacy on patients with BM is still unclear mainly due to the strict selection criteria adopted in clinical trials...
April 2018: Immunotherapy
C Ricordel, L Friboulet, F Facchinetti, J-C Soria
Lung cancer represents the leading cause of cancer-related deaths worldwide. Despite great advances in its management with the recent emergence of molecular targeted therapies for non-small-cell lung cancer (NSCLC), relapse of the metastatic disease always occurs within approximately one year. Epidermal growth factor receptor (EGFR) mutant tumours are the prime example of oncogene addiction and clonal evolution in oncology, regarding the emergence of resistance to first- and second-generation EGFR inhibitors...
January 1, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Aniello Cerrato, Roberta Visconti, Angela Celetti
Gene fusions occur in up to 17% of solid tumours. Oncogenic kinases are often involved in such fusions. In lung cancer, almost 30% of patients carrying an activated oncogene show the fusion of a tyrosine kinase to an heterologous gene. Several genes are partner in the fusion with the three kinases ALK, ROS1 and RET in lung. The impaired function of the partner gene, in combination with the activation of the kinase, may alter the cell signaling and promote the cancer cell addiction to the oncogene. Moreover, the gene that is partner in the fusion to the kinase may affect the response to therapeutics and/or promote resistance in the cancer cells...
February 19, 2018: Molecular Cancer
J Remon, N Vilariño, N Reguart
Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment strategy of advanced non-small cell lung cancer (NSCLC). Beyond the already approved indications in first- and second-line setting of advanced NSCLC, new data has recently emerged demonstrating its efficacy in locally advanced disease as maintenance after chemo-radiotherapy and currently several trials are also exploring its efficacy in earlier stages of the disease to evaluate whether these results could be extrapolated to the adjuvant setting...
February 8, 2018: Cancer Treatment Reviews
Hiroshi Kitamura, Hozumi Motohashi
The KEAP1-NRF2 system is a pivotal defense mechanism against oxidative and electrophilic stress. While transient NRF2 activation in response to stress is beneficial for health, persistent NRF2 activation in cancer cells has deleterious effects on cancer-bearing hosts by conferring therapeutic resistance and aggressive tumorigenic activity on cancer cells. Because NRF2 increases the anti-oxidant and detoxification capability of cancer cells, persistently high levels of NRF2 activity enhance therapeutic resistance of the cancer cells...
February 16, 2018: Cancer Science
Antonia Marazioti, Ioannis Lilis, Malamati Vreka, Hara Apostolopoulou, Argyro Kalogeropoulou, Ioanna Giopanou, Georgia A Giotopoulou, Anthi C Krontira, Marianthi Iliopoulou, Nikolaos I Kanellakis, Theodora Agalioti, Anastasios D Giannou, Celestial Jones-Paris, Yoichiro Iwakura, Dimitrios Kardamakis, Timothy S Blackwell, Stavros Taraviras, Magda Spella, Georgios T Stathopoulos
Malignant pleural effusion (MPE) is a frequent metastatic manifestation of human cancers. While we previously identified KRAS mutations as molecular culprits of MPE formation, the underlying mechanism remained unknown. Here, we determine that non-canonical IKKα-RelB pathway activation of KRAS-mutant tumor cells mediates MPE development and this is fueled by host-provided interleukin IL-1β. Indeed, IKKα is required for the MPE-competence of KRAS-mutant tumor cells by activating non-canonical NF-κB signaling...
February 14, 2018: Nature Communications
Adrien Costantini, Marta Grynovska, Francesca Lucibello, Jorge Moisés, Franck Pagès, Ming S Tsao, Frances A Shepherd, Hasna Bouchaab, Marina Garassino, Joachim G J V Aerts, Julien Mazières, Michele Mondini, Thierry Berghmans, Anne-Pascale Meert, Jacques Cadranel
In May 2017, the second European Respiratory Society research seminar of the Thoracic Oncology Assembly entitled "Immunotherapy, a new standard of care in thoracic malignancies?" was held in Paris, France. This seminar provided an opportunity to review the basis of antitumour immunity and to explain how immune checkpoint inhibitors (ICIs) work. The main therapeutic trials that have resulted in marketing authorisations for use of ICIs in lung cancer were reported. A particular focus was on the toxicity of these new molecules in relation to their immune-related adverse events...
February 2018: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
Philippe Marchetti, Anne Trinh, Raeeka Khamari, Jerome Kluza
BACKGROUND: Besides its influence on survival, growth, proliferation, invasion and metastasis, cancer cell metabolism also greatly influences the cellular responses to molecular-targeted therapies. SCOPE OF THE REVIEW: To review the recent advances in elucidating the metabolic effects of BRAF and MEK inhibitors (clinical inhibitors of the MAPK/ERK pathway) in melanoma and discuss the underlying mechanisms involved in the way metabolism can influence melanoma cell death and resistance to BRAF and MEK inhibitors...
January 31, 2018: Biochimica et Biophysica Acta
Shu Zhou, Guo-Bo Li, Lin Luo, Lei Zhong, Kai Chen, Hui Li, Xiao-Juan Jiang, Qi Fu, Xin Long, Jin-Ku Bao
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and plays a key functional role in various cancer cells. Although MELK may not be a cancer addiction target, the development of specific MELK inhibitors would provide useful chemical tools for synthetic lethal investigation. Herein, we identified several hit compounds using a customized structure-based virtual screening, among which compounds 4 and 16 showed the most potent inhibition to MELK with IC50 values of 3...
February 7, 2018: Organic & Biomolecular Chemistry
Cesare Gridelli, Paul Baas, Fabrice Barlesi, Fortunato Ciardiello, Lucio Crinò, Enriqueta Felip, Shirish Gadgeel, Vali Papadimitrakopoulou, Luis Paz-Ares, David Planchard, Maurice Perol, Nasser Hanna, Assunta Sgambato, Francesca Casaluce, Filippo de Marinis
Non-small-cell lung cancer (NSCLC) patients inevitably progress to first-line therapy and further active treatments are warranted. In the past few years, new second-line therapies, beyond chemotherapy agents, have become available in clinical practice. To date, several options for the second-line treatment of non-oncogene-addicted NSCLC patients ranging from chemotherapy in combination with antivascular endothelial growth factor receptor to immunotherapeutics are available. In oncogene-driven tumors, the better knowledge of mechanisms of acquired resistance to earlier tyrosine kinase inhibitors is leading to novel active inhibitors now available/in development...
December 22, 2017: Clinical Lung Cancer
Samaresh Sau, Hashem O Alsaab, Ketki Bhise, Rami Alzhrani, Ghazal Nabil, Arun K Iyer
Several cancer immunotherapy approaches have been recently introduced into the clinics and they have shown remarkable therapeutic potentials. The groundbreaking cancer immunotherapeutic agents function as a stimulant or modulator of the body immune system to fight against or kill cancers. Although targeted immunotherapies such as immune check point inhibitors (CTLA-4 or PD-1/PD-L1), DNA vaccination and CAR-T therapy are revolutionizing cancer treatment, the delivery efficacy can be further improved while their off-target toxicity can be mitigated through nanotechnology approaches...
January 29, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Francesco Jacopo Romano, Elia Guadagno, Domenico Solari, Giorgio Borrelli, Sara Pignatiello, Paolo Cappabianca, Marialaura Del Basso De Caro
Glioblastoma is one of the most malignant cancers, with a distinguishing dismal prognosis: surgery followed by chemo- and radiotherapy represents the current standard of care, and chemo- and radioresistance underlie disease recurrence and short overall survival of patients suffering from this malignancy. ATM is a kinase activated by autophosphorylation upon DNA doublestrand breaks arising from errors during replication, byproducts of metabolism, chemotherapy or ionizing radiations; TP53 is one of the most popular tumor suppressor, with a preeminent role in DNA damage response and repair...
January 25, 2018: Journal of Cellular Biochemistry
Taku Sato, Mami Morita, Ryota Tanaka, Yui Inoue, Miyuki Nomura, Yoshimi Sakamoto, Koh Miura, Shigemi Ito, Ikuro Sato, Nobuyuki Tanaka, Jiro Abe, Satomi Takahashi, Masaaki Kawai, Masami Sato, Yoshitaka Hippo, Hiroshi Shima, Yoshinori Okada, Nobuhiro Tanuma
Lung cancer is the most common cause of cancer mortality, however, efficient methods to culture, expand and transform lung epithelial (LE) cells have not been established. In the present study, an efficient ex vivo method was applied to recapitulate lung carcinogenesis using mouse LE cells. A Matrigel-assisted three-dimensional culture was used to isolate and selectively expand LE cells from mouse lungs. Purified LE cells were passaged and expanded for at least 2 to 3 months while maintaining epidermal growth factor-dependence...
December 2017: Oncology Letters
Roberto Ferrara, Laura Mezquita, Benjamin Besse
The treatment paradigm of NSCLC underwent a major revolution during the course of 2017. Immune checkpoint inhibitors (ICIs) brought remarkable improvements in response and overall survival both in unselected pretreated patients and in untreated patients with programmed death ligand 1 expression of 50% or more. Furthermore, compelling preliminary results were reported for new combinations of anti-programmed cell death 1/programmed death ligand 1 agents with chemotherapy or anti-cytotoxic T-lymphocyte associated protein 4 inhibitors...
March 2018: Journal of Thoracic Oncology
Ying Dai, Quanxiang Wei, Christian Schwager, Janina Hanne, Cheng Zhou, Klaus Herfarth, Stefan Rieken, Kenneth E Lipson, Jürgen Debus, Amir Abdollahi
BACKGROUND: Patients with Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) positive lung cancer are sensitive to ALK-kinase inhibitors. TAE684 is a potent second generation ALK inhibitor that overcomes Crizotinib resistance. Radiotherapy is an integral therapeutic component of locally advanced lung cancer. Therefore, we sought to investigate the effects of combined radiotherapy and ALK-inhibition via TAE684 in ALK-positive vs. wild type lung cancer cells...
January 5, 2018: Radiation Oncology
Cornelis M van Tilburg, Florian Selt, Felix Sahm, Heidi Bächli, Stefan M Pfister, Olaf Witt, Till Milde
Infants with low-grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children...
March 2018: Pediatric Blood & Cancer
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