Overcoming chemoresistance in cancer by manipulating lysosomal function

• Applicant: Dr. Karin Bartel
• Subject Area: Pharmacy
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466015231

Chemoresistance, i.e. the unresponsiveness to treatment with several, structurally unrelated drugs, is a major reason for treatment failure in cancer therapy. Yet, efforts to overcome this problem or to chemosensitize cells, show limited success due to an incomplete understanding of the vast underlying mechanisms. Described mechanisms are mainly impaired drug uptake, mutations of drug targets, and increased drug efflux via efflux transporters (e.g. MRP1, BCRP or MDR1/P-gp). Interestingly, the lysosome, a membrane-bound degradation organelle with an acidic interior, has emerged as a novel target in cancer research and might also provide the potential to overcome chemoresistance. Increasing data suggest, that it is important for P-gp trafficking and the so-called drug safe house effect, a phenomenon in which cytostatic weak bases are sequestered within the acidic lumen. Importantly, several lysosomal surface proteins, such as transporters and ion channels, make them druggable and provide cancer specificity. Based on the hypothesis, that lysosomes essentially contribute to the development and persistence of chemoresistance, we will conduct our research. In preliminary data, we have validated a leukemic resistance model. Analysis of different lysosomal housekeeping genes indicated a concomitant change of lysosomes along with the resistance phenotype. Especially two-pore channels (TPC) are upregulated in the resistant subline, most prominent the lysosomal cation channel TPC2, which has already been reported to be important for cancer cells. Generation of a TPC2 knock-out (KO) in the resistant subline enabled us to investigate its role in chemoresistance. Our data show that TPC2 KO sensitizes resistant leukemic cells towards cytostatic treatment and impairs P-gp trafficking. However, many mechanistic questions remain, e.g.: Which lysosomal genes in general can cause chemosensitization? How do they contribute to resistance? How can we exploit the knowledge for novel therapies in pre-clinical models? We will address these questions in several ways. By performing a methodically, broad and unbiased screening we want to identify lysosomal genes implicated in chemoresistance and verify as well as mechanistically study them in different resistance models. The obtained knowledge will then be used to investigate the potential of known pharmacological modulators of lysosomal function to be combined with classical chemotherapeutics as novel strategies. After assessing underlying mechanisms for the chemosensitizing potential we will transfer our findings to pre-clinical models to push the knowledge one step further from bench to bedside.

• DFG Programme: Research Grants