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Drug Resistance and membrane proteins (DRMP) (P. Falson)

The “Drug Resistance Mechanism and Modulation” group is studying the molecular and cellular mechanism of multidrug ABC (“ATP-binding cassette”) transporters which are responsible for cellular resistance to multiple chemotherapeutics. These membrane transporters are overexpressed in cancer cells [P-gp (“P-glycoprotein”)/ABCB1, MRP1 (“multidrug resistance protein”)/ABCC1 and BCRP (“breast cancer resistance protein”)/ABCG2] and confer resistance to anticancer drugs. Similar transporters such as BmrA, in Bacillus subtilis bacteria, or CDR1 and CDR2, in the pathogenic yeast Candida albicans, are involved in resistance to antibiotics or antifungals. P-gp and MRP1, as well as CDR1 and CDR2, are “full transporters” containing two homologous halves, while BmrA and BCRP are “half transporters” functioning as homodimers.

The aims are of two types : on the one hand to elucidate at both molecular and cellular levels the mechanism of chemotherapeutics transport, which is coupled to ATP hydrolysis, and on the other hand to identify modulators with selectivity for each transporter. Such modulators, optimized in vitro through “ligand-based drug design”, are inhibitors altering the pathological activity of drug efflux and then reverting the multidrug resistance phenotype (as illustrated for P-gp and BCRP). By contrast, other modulators are stimulating the efflux activity promoting a selective apoptosis of cancer cells (as illustrated for MRP1): they induce collateral sensitivity of targeted cancer cells overexpressing a multidrug ABC transporter which constitutes their Achilles’heel within such a strategy. The in vivo activity of modulators is tested on mice carrying xenografts expressing the different human transporters.

Another approach, of “structure-based drug design”, is to crystallize the purified transporters, upon extraction and stabilization by suited detergents such as C4Cn calixarenes (illustration), in order to obtain a high-resolution crystal structure of fully-functional proteins. The promising results obtained with BmrA suggest a good feasibility with BCRP. Co-crystallization with modulators, coupled to detailed studies on enzymatic properties, will allow the design of new-generation modulators, further potent and selective.

The group is certified by the French National League against Cancer : 1st contract from 2009 to 2011, 2nd contract from 2012 to 2014.