Abstract PR02: LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6– Reactivating Rb in cancer.

Abstract

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.

The Role of CDK4/6 Inhibition in Breast Cancer

“…In preclinical tumor models, LEE011 has demonstrated a dose-dependent antitumor activity that tracks well with CDK4/6 inhibition [60]. As with palbociclib, tumor regression was seen in some in vivo models.…”

Targeting CDK6 in cancer: State of the art and new insights

“…Mechanistically, these drug candidates inhibit CDK4/6, halt Rb phosphorylation and arrest G1 cell cycle progression of cancer cells. 51,[90][91][92][93] PD0332991 has also demonstrated to cause almost identical senescence phenotypes as the endogenous CDK inhibitors p16 INK4a and p21 Cip1 do. 94 PD0332991 is a pyridopyrimidine derivative ( Table 2) developed by Pfizer with relative high level of selectivity toward CDK4 and CDK6.…”

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

“…In addition, ribociclib caused cell-cycle arrest and senescence in a series of human neuroblastoma-derived cell lines (particularly those harboring MYCN amplification; ref. 16), and treatment of both neuroblastoma and MRT subcutaneous xenograft models resulted in tumor growth delays (15,16). Collectively, these findings led to the hypothesis that ribociclib may have activity in neuroblastoma and MRTs with CDK4/6 activation through p16 loss or CCND1, CDK4, or CDK6 amplification.…”

“…Therefore, targeting cyclin D1 or the cyclin D-CDK4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) axis is a biologically rational strategy for inhibiting neuroblastoma and MRT growth. Ribociclib (LEE011) is an orally bioavailable, highly specific inhibitor of CDK4/6 (15). In vitro screens of a panel of more than 500 cell lines constituting the Novartis Cancer Cell Line Encyclopedia identified neuroblastoma and MRT cell lines to be among the most sensitive to ribociclib treatment (15).…”

“…Ribociclib (LEE011) is an orally bioavailable, highly specific inhibitor of CDK4/6 (15). In vitro screens of a panel of more than 500 cell lines constituting the Novartis Cancer Cell Line Encyclopedia identified neuroblastoma and MRT cell lines to be among the most sensitive to ribociclib treatment (15). In addition, ribociclib caused cell-cycle arrest and senescence in a series of human neuroblastoma-derived cell lines (particularly those harboring MYCN amplification; ref.…”