Selected alkylating agents can overcome drug tolerance of G0-like tumor cells and eradicate BRCA1-deficient mammary tumors in mice.

Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse.<br /><br />Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53-mutant breast cancer. Due to the large intragenic deletion of the Brca1 gene, no restoration of BRCA1 function is possible, and therefore no BRCA1-dependent acquired resistance occurs. To characterize the cell cycle stage from which Brca1^-/-;p53^-/- mammary tumors arise after cisplatin treatment, we introduced the fluorescent ubiquitination-based cell cycle indicator (FUCCI) construct into the tumor cells.<br /><br />Results: Despite repeated sensitivity to the maximum tolerated dose (MTD) of platinum drugs, the Brca1-mutated mammary tumors are not eradicated, not even by a frequent dosing schedule. We show that relapse comes from single nucleated cells delaying entry into S phase. Such slowly cycling cells, which are present within the drug-naïve tumors, are enriched in tumor remnants. Using the FUCCI construct we identified non-fluorescent G₀-like cells as the population most tolerant to platinum drugs. Intriguingly, these cells are more sensitive to the DNA crosslinking agent nimustine resulting in an increased number of multinucleated cells that lack clonogenicity. This is consistent with our in vivo finding that the nimustine MTD, among several alkylating agents, is most effective in eradicating Brca1-mutated mouse mammary tumors.<br /><br />Conclusions: Our data show that targeting G₀-like cells is crucial for the eradication of BRCA1/p53-deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine.

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