Abstract 2309: Increase in Cdk4 activity during progression of small intestinal neuroedocrine tumors

In the USA, there are approximately 5000 new cases of small intestinal neuroendocrine tumors (SINETs) per year, many of which already show liver metastasis upon initial diagnosis. The genetic causes of SINETs have long been a mystery. The only known recurrent mutations are in the Cdkn1b gene, which is mutated in 8% of tumors. Cdkn1b encodes p27kip1, an inhibitor of Cdk4 and Cdk2. We analyzed proteins and genes linked to the function of Cdk4 in a set of early and late SINETs (pathological stages M0 or M1). Amplification of Cdk4 activators (CcnD1, CcnD2, CcnD3), or loss of copy of Cdk4 inhibitors (Cdkn1b as well as Cdkn2a), or mutation of Cdkn1b were uncommon events, but notably occurred almost exclusively in patients with late stage disease. Patients with late stage tumors also had genetic abnormalities in Phlda3, including loss of copy, loss of heterozygosity, or presence of the rs35383942 SNP. Altogether, more than 50 percent of the advanced tumors had one or more of these genetic events, compared to less than 15 percent of the early tumors. Phlda3 is known to affect Akt activity which in turn is known to repress p27kip1 by phosphorylation, and indeed we detected more p27kip1 phosphorylation in late stage tumors. Finally, advanced tumors showed higher expression of Cdk4 and increased phosphorylation of serine-807 or serine-811 of the Rb1 protein. Together, these data argue that there is genetic pressure to increase Cdk4 activity during progression of SINETs, and suggest that patients with advanced SINETs may respond to Cdk4 inhibitors. Citation Format: Tanupriya Contractor, Chris R. Harris. Increase in Cdk4 activity during progression of small intestinal neuroedocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2309.