fig8

Figure 8. Major pathways that lead to the development of alternative drug resistance mechanisms (ADR) in human cancers. A: the model is based on the evidence from K562/R7, RVC, RDC and other drug-resistant cell lines (described in both Tables 1 and 2). The model depicts that the low to no mutational events of the ABCB1 coding regions lead to expression or overexpression of wild-type ABCB1/P-gp, whose functional inhibition and partial inhibition encourage the development of stable and unstable ADR mechanisms, respectively; B: therapeutic strategies related to clinical trials that target ABC transporters. CsA: cyclosporine; RA: gene rearrangements; Inh: inhibition; mut: mutant(s); P1: the native ABCB1 promoter located at exon 1 of the gene; P2: the far upstream ABCB1 promoter located at exon -1 of the gene; P-gp: P-glycoprotein; PSC: SDZ PSC-833 known as valspodar; TPs: transporters; VX-770: the potentiator drug VX-770 (known as ivacaftor) that targets the CFTR-G551D mutation; VX-809: the corrector drug VX-809 (lumacaftor) that targets the CFTR-F508del mutation