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CDK 4/6 Inhibitors Sensitize PIK3CA Mutant Breast Cancer to PI3K Inhibitors

2014; Cell Press; Volume: 26; Issue: 1 Linguagem: Inglês

10.1016/j.ccr.2014.05.020

1878-3686

Sadhna Vora, Dejan Juric, Nayoon Kim, Mari Mino‐Kenudson, Tiffany G. Huynh, Carlotta Costa, Elizabeth L. Lockerman, Sarah F. Pollack, Manway Liu, Xiaoyan Li, Joseph Lehár, Marion Wiesmann, Markus Wartmann, Yan Chen, Z. Alexander Cao, Maria Pinzon-Ortiz, Sunkyu Kim, Robert Schlegel, Alan Huang, Jeffrey A. Engelman,

Chronic Lymphocytic Leukemia Research

Activation of the phosphoinositide 3-kinase (PI3K) pathway occurs frequently in breast cancer. However, clinical results of single-agent PI3K inhibitors have been modest to date. A combinatorial drug screen on multiple PIK3CA mutant cancers with decreased sensitivity to PI3K inhibitors revealed that combined CDK 4/6-PI3K inhibition synergistically reduces cell viability. Laboratory studies revealed that sensitive cancers suppress RB phosphorylation upon treatment with single-agent PI3K inhibitors but cancers with reduced sensitivity fail to do so. Similarly, patients’ tumors that responded to the PI3K inhibitor BYL719 demonstrated suppression of pRB, while nonresponding tumors showed sustained or increased levels of pRB. Importantly, the combination of PI3K and CDK 4/6 inhibitors overcomes intrinsic and adaptive resistance leading to tumor regressions in PIK3CA mutant xenografts.