Small cell lung cancer (SCLC) represents ∼15% of all lung cancer diagnoses in the US and has a particularly poor prognosis. We hypothesized that kinases regulating SCLC survival pathways represent therapeutically targetable vulnerabilities whose inhibition may improve SCLC outcome. A shRNA library targeting all human kinases was introduced into seven chemonaive patient derived xenografts (PDX), and cells cultured in vitro and in vivo. On harvest, lost, or depleted, shRNAs were considered as regulating cell survival pathways, and deemed essential kinases. Unsupervised hierarchical cluster analysis of recovered shRNAs separated the PDX into two clusters suggesting kinase based heterogeneity among the SCLC PDX. ... More
Small cell lung cancer (SCLC) represents ∼15% of all lung cancer diagnoses in the US and has a particularly poor prognosis. We hypothesized that kinases regulating SCLC survival pathways represent therapeutically targetable vulnerabilities whose inhibition may improve SCLC outcome. A shRNA library targeting all human kinases was introduced into seven chemonaive patient derived xenografts (PDX), and cells cultured in vitro and in vivo. On harvest, lost, or depleted, shRNAs were considered as regulating cell survival pathways, and deemed essential kinases. Unsupervised hierarchical cluster analysis of recovered shRNAs separated the PDX into two clusters suggesting kinase based heterogeneity among the SCLC PDX. Twenty-three kinases were identified as essential in two or more PDX, with mTOR a candidate essential kinase in four. mTOR phosphorylation (p-mTOR) status correlated with PDX sensitivity to mTOR kinase inhibition, and mTOR inhibition sensitized PDX to cisplatin/etoposide. In PDX where mTOR was defined as essential, mTOR inhibition caused a 43% decrease in tumor volume at 21 days (P<0.01). Combining mTOR inhibition with cisplatin/etoposide decreased PDX tumor volume 96% compared to cisplatin/etoposide alone at 70 days (P<0.002). Chemoresistance did not develop with the combination of mTOR inhibition and cisplatin/etoposide in mTOR essential PDX over 105 days. The prevalence of p-mTOR in a tissue microarray of chemonaive SCLC was 27% identifying a significant SCLC subtype that might benefit by the addition of mTOR inhibition to standard chemotherapy. These studies show that kinases can define SCLC subgroups, can identify therapeutic vulnerabilities, and can potentially be used to optimize therapeutic approaches.
