Abstract 2590: A novel use of E2f and Cdk inhibitors to prevent RB-null tumours in genetically engineered models of retinoblastoma

Abstract

Abstract Over the past few decades, extensive mouse and human genetics have implicated deregulated E2f and Cdk activity in cell exit escape and tumorigenesis. In flies, activating E2f or Cdk causes temporary abnormal division, but both must be induced for long-term aberrant proliferation - a hallmark in benign tumor-prone lesions. Almost invariably, defects in the Rb-E2f or Cip/Kip Cdk inhibitor (CKI)-Cdk2/1 cell cycle regulatory pathways occur together in human cancer. Despite this, little is known in regards to whether dual activation is an obligate feature for tumor susceptibility at initiation in vivo. In human retinoblastoma, homozygous RB1 inactivation is sufficient to initiate the disease. However, mouse retinoblastoma requires inactivation of both Rb1 and one of its family members (p107 or p130). Like pRb, p107 and p130 are best known as E2f inhibitors. Unexpectedly, the additional loss of p107 does not elevate E2f targets follow Rb loss. Instead, Rb/p107-deficient cells induce the E3 ubiquitin ligase Skp2 and activate Cdk2 in vivo. Strikingly, Cdk2 activity tightly correlates with susceptibility to retinoblastoma in our mouse models. Compiling this data, tumorigenesis may have two distinct steps: (1) Rb loss initiates abnormal division, and (2) the additional loss of p107 or, as we have found, p27kip1, both of which lead to Cdk2 activation is required to engender cancer susceptibility. Together, E2f and Cdk dual axes activity is essential for retinoblastoma initiation. To test this notion pharmaceutically, we treated retinoblastoma-prone mice with a Cdk or E2f small molecule inhibitor during the birth period of suspected cancer cell-of-origin. Strikingly, one-week exposure to an inhibitor of either axes curtailed retinoblastoma in Rb/p107- null and Rb/p27-null retinas. These therapeutic successes were achieved without disrupting normal proliferation. Thus, E2f inhibitors, untested in vivo, or Cdk inhibitors, largely unproven as therapeutics, may be ideal chemopreventative agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2590. doi:1538-7445.AM2012-2590