Chemical Biology

Identification of Subtype-selective Vulnerabilities and Biomarkers in Non-small Cell Lung Cancer

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  Bruce Posner, PhD

  Professor
  UT Southwestern Medical Ctr

Lung cancer is the leading cause of cancer-related deaths with more than 1.3 MM people dying of this disease each year. Drs. John Minna and Adi Gazdar have collected over 100 non-small cell lung cancer (NSCLC) tumor samples and created corresponding cell lines that they have characterized by molecular and biological methods. From these studies and others, we postulated that lung cancer can be characterized as a collection of diseases, each distinguished by unique biomarkers and chemical vulnerabilities. Using a chemistry-first approach, we carried out high throughput, phenotypic screens of 12 representative lung cancer cell lines from our NSCLC panel against the UT Southwestern chemical library (~230,000 compounds). In follow up studies, we identified ~180 small molecule toxins representing over 30 chemical series that are toxic to subsets of the extended lung cancer cell panel (~105 cell lines) but not to immortalized human bronchial epithelial cells (HBEC’s). We have developed and used bioinformatics tools (machine learning and a novel variation of the Kolmogorov-Smirnov statistic) in conjunction with orthogonal molecular data sets (e.g. somatic mutations, gene expression, protein expression, metabolic flux, etc.) to identify biomarker hypotheses that have provided insights into mechanism of action and possible targets of these cancer subtype-selective compounds. Subsequent biochemical, cell based, and in vivo studies on selected compounds have identified several novel target/biomarker relationships that may have therapeutic impact.