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Simple Summary  Real-time ex vivo drug testing tailors individual therapeutics based on predicted drug responses. Most technologies to date rely on conventional drug screening that provides low confidence data. Here, we present high-content analysis-based drug testing of glioblastoma patients to identify the right glioblastoma patients for a given drug. This generates multi-parameter biomarker and phenotype readouts providing a better reliability of the assay. Additionally, we showed a high-content drug repurposing screen and defined a new c-Met-inhibiting function of the CDK4/6 inhibitor Abemaciclib. Large-scale high throughput screening results demonstrate that Abemaciclib sensitivity in glioblastoma patients is highly correlated with the c-Met inhibitors sensitivity, further supporting the accuracy of the platform and important new clinical implications regarding multiple functions of Abemaciclib.    Abstract  (1) Background: Recent advances in precision oncology research rely on indicating specific genetic alterations associated with treatment sensitivity. Developing ex vivo systems to identify cancer patients who will respond to a specific drug remains important. (2) Methods: cells from 12 patients with glioblastoma were isolated, cultured, and subjected to high-content screening. Multi-parameter analyses assessed the c-Met level, cell viability, apoptosis, cell motility, and migration. A drug repurposing screen and large-scale drug sensitivity screening data across 59 cancer cell lines and patient-derived cells were obtained from 125 glioblastoma samples. (3) Results: High-content analysis of patient-derived cells provided robust and accurate drug responses to c-Met-targeted agents. Only the cells of one glioblastoma patient (PDC6) showed elevated c-Met level and high susceptibility to the c-Met inhibitors. Multi-parameter image analysis also reflected a decreased c-Met expression and reduced cell growth and motility by a c-Met-targeting antibody. In addition, a drug repurposing screen identified Abemaciclib as a distinct CDK4/6 inhibitor with a potent c-Met-inhibitory function. Consistent with this, we present large-scale drug sensitivity screening data showing that the Abemaciclib response correlates with the response to c-Met inhibitors. (4) Conclusions: Our study provides a new insight into high-content screening platforms supporting drug sensitivity prediction and novel therapeutics screening.

High-Content Analysis-Based Sensitivity Prediction and Novel Therapeutics Screening for c-Met-Addicted Glioblastoma