In the second study, patients with solid tumors were treated with the pan-CDK inhibitor PHA-793887 in a phase I clinical trial. Seven patients from that trial were subjected to gene expression profiling of biopsies pre-treatment and on-treatment using Agilent microarrays (Locatelli et al., 2010; Massard et al., 2011). For each patient, the on-treatment expression profile was compared to their pre-treatment profile and the difference used as a signature to query the the CMap. This analysis showed an association between duration of therapy (a proxy for clinical benefit) and connectivity to the overexpression of key negative regulators of the cell cycle such as CDKN1A and CDKN2A. Strong connectivity was also observed to knock-down of the cyclin-dependent kinase CDK4 – one of the targets of the drug (Figure 7C). Interestingly, the patients with rapidly progressive disease showed anti-correlation to this cell cycle inhibition signature, possibly reflective of a feedback mechanism to reactivate the cell cycle in the face of CDK4 inhibition. These results, while reflecting only a small number of patients, are encouraging. First, they suggest that while PHA-793887 may be a
