Abstract
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.
Highlights
The efficacy of targeted therapy, a personalized medicine based on the molecular features of each tumor, is highly affected by the onset of primary or secondary resistance [1,2,3,4,5,6]
Cancer [10], Melanoma [11,12], Lung Cancer [13]. All these models have two features in common: the tumor is driven by a single, potent oncogene necessary to the tumorigenic process and resistance arises from oncogene overexpression
Upon drug withdrawal we observed a first drop in cell number and viability in both cell lines (Figure 1A,B, Figure S1)
Summary
The efficacy of targeted therapy, a personalized medicine based on the molecular features of each tumor, is highly affected by the onset of primary or secondary resistance [1,2,3,4,5,6]. In the past few years, some groups observed in pre-clinical models that resistance to tyrosine kinase inhibitors may be associated with the development of drug addiction, meaning that upon drug withdrawal, resistant cells die. It is likely that a subset of patients relapsing on TKI therapy because of oncogene overexpression, one of the main causes of relapse, may benefit from drug interruption more than from drug increase or drug change. This option would be effective, and safe, since side effects are lacking, and with full compliance. Very little is known about the molecular mechanisms driving drug addiction
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