Next Article in Journal
Use of Germline Genetic Variability for Prediction of Chemoresistance and Prognosis of Breast Cancer Patients
Previous Article in Journal
Management of Typical and Atypical Pulmonary Carcinoids Based on Different Established Guidelines
Open AccessArticle

Mitochondrial Hyperactivation and Enhanced ROS Production are Involved in Toxicity Induced by Oncogenic Kinases Over-Signaling

Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milano, Italy
Tettamanti Research Centre, Pediatric Clinic, c/o Nuovo Osp.San Gerardo, 20900 Monza, Italy
Author to whom correspondence should be addressed.
Cancers 2018, 10(12), 509;
Received: 6 November 2018 / Revised: 30 November 2018 / Accepted: 7 December 2018 / Published: 12 December 2018
Targeted therapy is an effective, rational, and safe approach to solid and hematological tumors treatment. Unfortunately, a significant fraction of patients treated with tyrosine kinase inhibitors (TKI) relapses mainly because of gene amplification, mutations, or other bypass mechanisms. Recently a growing number of papers showed how, in some cases, resistance due to oncogene overexpression may be associated with drug addiction: cells able to proliferate in the presence of high TKI doses become also TKI dependent, undergoing cellular stress, and apoptosis/death upon drug withdrawal. Notably, if a sub-cellular population survives TKI discontinuation it is also partially re-sensitized to the same drug. Thus, it is possible that a subset of patients relapsing upon TKI treatment may benefit from a discontinuous therapeutic schedule. We focused on two different hematologic malignancies, chronic myeloid leukemia (CML) and anaplastic large cell lymphoma (ALCL), both successfully treatable with TKIs. The two models utilized (LAMA and SUP-M2) differed in having oncogene overexpression as the sole cause of drug resistance (CML), or additionally carrying kinase domain mutations (ALCL). In both cases drug withdrawal caused a sudden overload of oncogenic signal, enhanced mitochondria activity, induced the release of a high amount of reactive oxygen species (ROS), and caused genotoxic stress and massive cell death. In LAMA cells (CML) we could rescue the cells from death by partially blocking downstream oncogenic signaling or lowering ROS detrimental effect by adding reduced glutathione. View Full-Text
Keywords: cancer; oncogene; inhibitors; personalized medicine; targeted therapy cancer; oncogene; inhibitors; personalized medicine; targeted therapy
Show Figures

Figure 1

MDPI and ACS Style

Ceccon, M.; Mauri, M.; Massimino, L.; Giudici, G.; Piazza, R.; Gambacorti-Passerini, C.; Mologni, L. Mitochondrial Hyperactivation and Enhanced ROS Production are Involved in Toxicity Induced by Oncogenic Kinases Over-Signaling. Cancers 2018, 10, 509.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Back to TopTop