He Wei, Demas Diane M, Kraikivski Pavel, Shajahan-Haq Ayesha N, Baumann William T
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia, USA.
Division of Systems Biology, Academy of Integrated Science, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
bioRxiv. 2024 Sep 19:2024.09.15.613122. doi: 10.1101/2024.09.15.613122.
Although endocrine therapies and Cdk4/6 inhibitors have produced significantly improved outcomes for patients with estrogen receptor positive (ER+) breast cancer, continuous application of these drugs often results in resistance. We hypothesized that cancer cells acquiring drug resistance might increase their dependency on negative regulators of the cell cycle. Therefore, we investigated the effect of inhibiting WEE1 on delaying the development of resistance to palbociclib and fulvestrant. We treated ER+ MCF7 breast cancer cells with palbociclib alternating with a combination of fulvestrant and a WEE1 inhibitor AZD1775 for 12 months. We found that the alternating treatment prevented the development of drug resistance to palbociclib and fulvestrant compared to monotherapies. Furthermore, we developed a mathematical model that can simulate cell proliferation under monotherapy, combination or alternating drug treatments. Finally, we showed that the mathematical model can be used to minimize the number of fulvestrant plus AZD1775 treatment periods while maintaining its efficacy.
尽管内分泌疗法和Cdk4/6抑制剂已显著改善了雌激素受体阳性（ER+）乳腺癌患者的治疗效果，但持续使用这些药物往往会导致耐药性。我们推测，获得耐药性的癌细胞可能会增加对细胞周期负调节因子的依赖性。因此，我们研究了抑制WEE1对延缓对哌柏西利和氟维司群耐药性发展的影响。我们用哌柏西利交替联合氟维司群和WEE1抑制剂AZD1775处理ER+ MCF7乳腺癌细胞12个月。我们发现，与单一疗法相比，交替治疗可预防对哌柏西利和氟维司群的耐药性发展。此外，我们建立了一个数学模型，该模型可以模拟单一疗法、联合疗法或交替药物治疗下的细胞增殖。最后，我们表明该数学模型可用于在保持疗效的同时，尽量减少氟维司群加AZD1775的治疗周期数。
