SCLC represents 15% of all lung cancer diagnoses in the United States and has a particularly poor prognosis. We hypothesized that kinases regulating SCLC survival pathways represent therapeutically targetable vulnerabilities whose inhibition may improve SCLC outcome.
Methods
A short-hairpin RNA (shRNA) library targeting all human kinases was introduced in seven chemonaive patient-derived xenografts (PDX) and the cells were cultured in vitro and in vivo. On harvest, lost or depleted shRNAs were considered as regulating-cell survival pathways and deemed essential kinases.
Results
Unsupervised hierarchical cluster analysis of recovered shRNAs separated the PDXs into two clusters, suggesting kinase-based heterogeneity among the SCLC PDXs. A total of 23 kinases were identified as essential in two or more PDXs, with mechanistic Target of Rapamycin (mTOR) a candidate essential kinase in four. mTOR phosphorylation status correlated with PDX sensitivity to mTOR kinase inhibition, and mTOR inhibition sensitized the PDX to cisplatin and etoposide. In the PDX in which 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 and etoposide decreased PDX tumor volume 96% compared with cisplatin and etoposide alone at 70 days (p < 0.002). Chemoresistance did not develop with the combination of mTOR inhibition and cisplatin and etoposide in mTOR-essential PDX over 105 days. The prevalence of phospho-mTOR-Ser-2448 in a tissue microarray of chemonaive SCLC was 27%, thus, identifying an important SCLC subtype that might benefit from the addition of mTOR inhibition to standard chemotherapy.
Conclusions
These studies reveal that kinases can define SCLC subgroups, can identify therapeutic vulnerabilities, and can potentially be used to optimize therapeutic approaches.
Significance
We used functional genomics to identify kinases regulating SCLC survival. mTOR was identified as essential in a subset of PDXs. mTOR inhibition decreased PDX growth, sensitized PDX to cisplatin and etoposide, and prevented chemoresistance.
Keywords
Functional genomics
Kinome
Kinase
mTOR
Small cell lung cancer
Cited by (0)
Drs. Kern and Kim contributed equally to this work.
Disclosure: Dr. Kern reports receiving support from the Antoinette E. (“Mimi”) & Herman Boehm Foundation Inc.; grants from the National Cancer Institute during the conduct of the study; and fees from other financial activities including Biodesix and Cireca, LLC. outside of the submitted work. Dr. Finigan reports receiving personal fees from EMD Serono and AstraZeneca outside of the submitted work. Dr. Dowlati reports receiving other fees and nonfinancial support from GlaxoSmithKline during the conduct of the study; grants from EMD Serono, Tesaro, Eli Lilly, Roche, Vertex, Regeneron, Millenium, Takeda, Ipsen, United Therapeutics, Mirati, Bristol-Myers Squibb, Incuron, Bayer; grants and personal fees from AbbVie, AstraZeneca, Seattle Genetics; and personal fees from Ariad outside of the submitted work. Dr. Rudin reports receiving personal fees from AbbVie, Amgen, Ascentage, AstraZeneca, Bicycle, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Jansen, Jazz, Eli Lilly/Loxo, Pfizer, PharmaMar, Syros, Vavotek, Bridge Medicines, and Harpoon Therapeutics outside of the submitted work. The remaining authors declare no conflict of interest.
