Precision medicine treatment for anticancer drug resistance

Chemoresistance remains a primary hindrance to curative cancer therapy. Whilst some mechanisms of chemoresistance have been characterized, molecular mechanisms of drug resistance remain elusive. As a step towards this end, we found that lysosomal sequestration of hydrophobic weak-base chemotherapeutics abolishes their accessibility to their cellular targets. This resulted in a markedly reduced cytotoxic activity and multidrug resistance (MDR). Hence, lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutics is a major mechanism of MDR. We further demonstrated that lysosomal sequestration of hydrophobic weak base drugs relies on the acidic pH of lysosomes, and triggers a TFEB-mediated lysosomal biogenesis, further enhancing drug sequestration and resistance. This was followed by lysosomal exocytosis, thereby extruding the entrapped drug cargo out of cancer cells. Thus, cancer cells with an increased number of drug-accumulating lysosomes, were markedly more resistant to multiple lysosome-sequestered chemotherapeutics, resulting in drug-induced, lysosome-mediated MDR. We therefore developed a novel modality of preclinical precision medicine termed lysosomal photodestruction by using lysosome-sequestered photosensitizers which generate reactive oxygen species, thereby surmounting MDR. In this webinar, Prof. Assaraf will address the role of acidic lysosomes in mediating a spectrum-wide cancer MDR as well as a novel Trojan horse precision medicine modality to surmount MDR.