Figure 10.

Description of the different phases of events justifying a combinatorial approach for treatment. (A) Maximal resistance (+++) is mediated by lysosomal trapping of sunitinib (yellow circles in lysosomes). The presence of autolysosomes (green circles) is indicative of incomplete autophagy. The proteasome degrades misfolded proteins and participates in recycling of amino acids. (B) The lysosome destabilizing agent Leu-Leu-O-Methyl (LLOM) prevents the trapping of sunitinib in lysosomes so the drug is localizes to the cytoplasm but is "taken in charge" by the ABCB1, which transport the drug out of the cell thus leading to intermediate resistance (++). (C) Maximal sensitivity to sunitinib can be obtained by 1) by destabilization of lysosomes with LLOM combined with inhibitors of ABC transporters (elacridar) or 2) with proteasome inhibitors (MG132 [mg] or bortezomib [borte]).