TY - JOUR
T1 - Selected alkylating agents can overcome drug tolerance of G 0 -like tumor cells and eradicate BRCA1-deficient mammary tumors in mice
AU - Pajic, Marina
AU - Blatter, Sohvi
AU - Guyader, Charlotte
AU - Gonggrijp, Maaike
AU - Kersbergen, Ariena
AU - Küçükosmanoğlu, Aslı
AU - Sol, Wendy
AU - Drost, Rinske
AU - Jonkers, Jos
AU - Borst, Piet
AU - Rottenberg, Sven
PY - 2017/11/15
Y1 - 2017/11/15
N2 - Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse. Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53-mutant breast cancer. Because of 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. Results: Despite repeated sensitivity to the MTD of platinum dmammary tumors ariserugs, 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 the S-phase. Such slowly cycling cells, which are present within the drug-na€ve tumors, are enriched in tumor remnants. Using the FUCCI construct, we identified nonfluorescent G 0 -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 the most effective in eradicating Brca1-mutated mouse mammary tumors. Conclusions: Our data show that targeting G 0 -like cells is crucial for the eradication of BRCA1/p53–deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine.
AB - Purpose: We aimed to characterize and target drug-tolerant BRCA1-deficient tumor cells that cause residual disease and subsequent tumor relapse. Experimental Design: We studied responses to various mono- and bifunctional alkylating agents in a genetically engineered mouse model for BRCA1/p53-mutant breast cancer. Because of 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. Results: Despite repeated sensitivity to the MTD of platinum dmammary tumors ariserugs, 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 the S-phase. Such slowly cycling cells, which are present within the drug-na€ve tumors, are enriched in tumor remnants. Using the FUCCI construct, we identified nonfluorescent G 0 -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 the most effective in eradicating Brca1-mutated mouse mammary tumors. Conclusions: Our data show that targeting G 0 -like cells is crucial for the eradication of BRCA1/p53–deficient tumor cells. This can be achieved with selected alkylating agents such as nimustine.
UR - http://www.scopus.com/inward/record.url?scp=85034850013&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1078-0432.CCR-17-1279
DO - https://doi.org/10.1158/1078-0432.CCR-17-1279
M3 - Article
C2 - 28821557
SN - 1078-0432
VL - 23
SP - 7020
EP - 7033
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -