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

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.