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

1
Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
2
Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milano, Italy
3
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; https://doi.org/10.3390/cancers10120509
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
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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.

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