Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes
Shideh Mirhadi, Shirley Tam, Quan Li, Nadeem Moghal, Nhu‐An Pham, Jiefei Tong, Brian Golbourn, Jonathan R. Krieger, Paul Taylor, Ming Li, Jessica Weiss, Sebastião N. Martins-Filho, Vibha Raghavan, Yasin Mamatjan, Aafaque Ahmad Khan, Michael Cabanero, Shingo Sakashita, Ku-Geng Huo, Sameer Agnihotri, Kota Ishizawa, Thomas K. Waddell, Gelareh Zadeh, Kazuhiro Yasufuku, Geoffrey Liu, Frances A. Shepherd, Michael F. Moran, Ming‐Sound Tsao
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbor actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. NSCLC and other cancers display profound proteome remodeling compared to normal tissue that is not predicted by DNA or RNA analyses. Here, we generate 137 NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Proteome analysis of the PDX models reveals 3 adenocarcinoma and 2 squamous cell carcinoma proteotypes that are associated with different patient outcomes, protein-phosphotyrosine profiles, signatures of activated pathways and candidate targets, and in adenocarcinoma, stromal immune features. These findings portend proteome-based NSCLC classification and treatment and support the PDX resource as a viable model for the development of new targeted therapies.