The tumor suppressor Retinoblastoma protein (Rb) is often inactivated in cancer. In many tumors, the Rb protein itself is retained but functionally inactivated by increased CDK4/6 kinase activity. A number of key oncogenic aberrations can result in this increased activity, including inactivation of CDKN2A (p16), translocation or amplification of D-cyclins, amplification of CDK4/6 and mutations/deletions upstream of cyclin D, such as activating mutations of BRAF/PIK3CA and PTEN deletion. Abolishing CDK4/6 kinase activity and subsequent reactivation of Rb in these tumors has been demonstrated to inhibit tumor initiation and growth. Here we will describe LEE011- an orally bioavailable, selective small molecule inhibitor of CDK4/6 kinases. LEE011 inhibits CDK4/6 kinase activity with nM IC50 and is highly selective for these targets. In a number of preclinical tumor models, LEE011 demonstrates a dose dependent anti-tumor activity that tracks well with CDK4/6 inhibition. The primary mechanism for growth inhibitory effect appears to be G1 arrest in vitro, although, in some sensitive in vivo models, regressions are observed. Importantly, given the role of CDK4/6 downstream of other oncogenic driver mutations, LEE011 shows single agent activity in melanomas with activating mutations of BRAF or NRAS, and in breast cancers with intact estrogen receptor and/or activating aberrations of PIK3CA/Her-2. Combining LEE011 with LGX818, a V600E BRAF specific inhibitor, leads to robust anti-tumor activity in melanoma models that are both sensitive and, importantly, those that are resistant to LGX818. Furthermore, combining LEE011 with BYL719, a PIK3CA specific inhibitor, also leads to significant anti-tumor activity in breast cancer models both sensitive and resistant to BYL719. Several clinical studies evaluating LEE011 as single agent and in combinations are underway.Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR02.Citation Format: Sunkyu Kim, Alice Loo, Rajiv Chopra, Giordano Caponigro, Alan Huang, Sadhna Vora, Sudha Parasuraman, Steve Howard, Nicholas Keen, William Sellers, Christopher Brain. LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6– Reactivating Rb in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR02.
CITATION STYLE
Kim, S., Loo, A., Chopra, R., Caponigro, G., Huang, A., Vora, S., … Brain, C. (2013). Abstract PR02: LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6– Reactivating Rb in cancer. Molecular Cancer Therapeutics, 12(11_Supplement), PR02–PR02. https://doi.org/10.1158/1535-7163.targ-13-pr02
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