A Proteomic Connectivity Map for Characterizing the Tumor Adaptive Response to Small Molecule Chemical Perturbagens.

Abstract

A powerful means to understand the cellular function of corrupt oncogenic signaling programs requires perturbing the system and monitoring the downstream consequences. Here, using a unique pair of non-small cell lung cancer (NSCLC)/normal lung epithelial patient-derived cell lines (HCC4017/HBEC30KT), we systematically interrogated the remodeling of the NSCLC proteome upon treatment with 35 chemical perturbagens targeting a diverse array of mechanistic classes. HCC4017 and HBEC30KT cells differ significantly in their proteomic response to the same compound treatment. Using protein covariance analyses, we identified a large number of functional protein networks. For example, we found that a poorly studied protein, C5orf22, is a novel component of the WBP11/PQBP1 splicing complex. Depletion of C5orf22 leads to the aberrant splicing and expression of genes involved in cell growth and immunomodulation. In summary, we show that by systematically measuring the tumor adaptive responses at the proteomic level, an understanding could be generated that provides critical circuit-level biological insights for these pharmacologic perturbagens.

• Authors: Zhenzhen Zi, Yajie Zhang, Peng Zhang, Qing Ding, Michael Chu, Yiwen Chen, John D Minna, Yonghao Yu
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 15 Issue 1 Pg. 140-150 (01 17 2020) ISSN: 1554-8937 [Electronic] United States
• PMID: 31846293 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Carrier Proteins
• Protein Kinase Inhibitors
• SIMC1 protein, human
• Protein Kinases

Topics

• Antineoplastic Agents (chemistry)
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Carrier Proteins (genetics, metabolism)
• Cell Line
• Cell Proliferation (drug effects, genetics)
• Drug Screening Assays, Antitumor
• Humans
• Immunomodulation (drug effects)
• Lung Neoplasms (drug therapy)
• Mutation (genetics)
• Oncogenes
• Protein Kinase Inhibitors (chemistry)
• Protein Kinases (metabolism)
• Proteomics (methods)
• Signal Transduction