Novel mechanisms of resistance to investigational molecularly targeted drugs

Drug resistance is a critical problem inhibiting the effective use of targeted molecular cancer therapies. Investigators have revealed a variety of resistance mechanisms, including alterations in drug targets, activation of pro-survival pathways, and the ineffective induction of cell death. The key alterations driving this resistance are likely condition-dependent, and a detailed analysis would be required to characterize these diverse alterations under a variety of conditions in order to facilitate practical precision medicine for treating individual cancer patients. We have been investigating the molecular mechanisms of anti-cancer drug resistance, and analyzed our original resistant cells against anti-mitotic kinase inhibitors. This study suggests that novel mechanisms reduce cytokinetic dysregulation caused by those inhibitors, and anti-apoptotic activities are associated with resistant phenotypes. These observations suggest that the activation of various bypass mechanisms may allow cancer cells to avoid the selective antiproliferative effect of molecularly targeted drugs, and such bypass activation mechanism would thus be a critical target for designing combination chemotherapy to overcome non-genetic drug resistance.