Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration

Abstract

Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients.

FGFR-TKI resistance in cancer: current status and perspectives

“…For example, ABCB1 has been reported to be a key player in resistance to the multiple-target kinase inhibitor Nintedanib [73,74]. Inhibition of ABCB1 and kinases simultaneously should be a promising strategy for overcoming resistance [75][76][77].…”

Tumor microenvironment and epithelial mesenchymal transition as targets to overcome tumor multidrug resistance

“…There is mounting evidence demonstrating a significant role of factors originating from tumor microenviroment (TME) for both responsiveness or resistance to various structurally and mechanistically unrelated anticancer drugs. The persistent production of inflammatory factors has been reported in TME-mediated EMT, metastasis and chemotherapy resistance (Acharyya et al, 2012;Bunt et al, 2006;Hartmann et al, 2005) (Gao et al, 2020;Krchniakova et al, 2020;Shaked, 2019). This may be due to inflammation-induced expansion and recruitment of macrophages and CD11b + /Gr-1 + myeloid-derived suppressor cells (MDSCs) (Szebeni et al, 2017;Xu et al, 2017) as well cancer-J o u r n a l P r e -p r o o f associated fibroblasts (CAFs) (Bharti et al, 2016).…”

The roles of the human ATP-binding cassette transporters P-glycoprotein and ABCG2 in multidrug resistance in cancer and at endogenous sites: future opportunities for structure-based drug design of inhibitors

“…In search of the Drugbank database of FDA-approved drugs, Lai et al [175] determined a set of 67 agents that have activity against P-gp but do not have anti-cancer activity. Interestingly, this list includes the anti-emetic/antipsychotic chlorpromazine [198] , the antibiotic macrolides erythromycin, azithromycin, and clarithromycin [199] , and the phosphodiesterases inhibitors sildenafil and vardenafil [200] .…”