Chlorambucil counteracts drug resistance in BRCA1/2-deficient cells and tumors
Tumours lacking BRCA1 or BRCA2 function with compromised homologous recombination (HR) repair accumulate genomic rearrangements conducive for tumorigenesis onset and progression. Remarkably, these defects can be exploited in the clinic to target specifically cancer cells, with PARP inhibitors as a prominent example. However, most tumours acquire resistance to therapies and therefore novel strategies for their elimination are needed. To identify new approaches, we performed a screen of a chemical library containing 1,250 FDA-approved drugs. Chlorambucil, a bifunctional alkylating agent routinely used in clinic for the treatment of chronic lymphocytic leukemia, was a top hit in our screens. We established that chlorambucil is toxic to BRCA1- or BRCA2-deficient human cells in 2D- and 3D-cultures. In addition, chlorambucil inhibited the growth of BRCA2-deficient xenografts established in mice. Importantly, chlorambucil was effective against PARP inhibitor-resistant cells and tumours. Cisplatin, an alkylating agent currently used in clinic, showed higher toxicity to BRCA1 cells than chlorambucil. Thus, chlorambucil may identify a novel approach for selective targeting of tumours carrying BRCA1/2 mutations, with lower toxicity to normal tissue than conventional therapies.
Genome Stability and Tumourigenesis Group, The CR-UK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, U.K.
Directeur de Recherche CNRS
Domain 2 - UMR 3244 - Dynamics of genetic Information