Significance This study validates a path toward personalized medicine that utilizes a survey of the effective signaling state of tumors via posttranslational modification analysis as a diagnostic alternative to direct examination of genetic mutations. Here, this approach is utilized to identify biomarkers for Cdk5-driven tumors. The same approach could be adapted to identify markers of other tumor drivers. As the number of cancer types in which Cdk5 is implicated is rising and as drugs with the potential to selectively target Cdk5 are moved toward the clinic, the translational potential of this diagnostic–therapeutic coupled system will be broad.