An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies

Abstract

Purpose Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells. Experimental Design We employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models. An NSCLC tissue pipeline combining patient-derived xenografts (PDXs) and ex vivo patient organotypic cultures has been established for treatment responsiveness assessment. Results We identified an ‘oncogene addiction phosphorylation signature’ (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments. Conclusions We propose a score derived from OAPS as a quantitative measure to evaluate oncogene addiction of cancer cell samples. This work underlines the importance of protein phosphorylation assessment for patient stratification in precision oncology and corresponding identification of tumor subtypes sensitive to inhibition of a particular oncogene.

E2F1-Associated Purine Synthesis Pathway Is a Major Component of the MET-DNA Damage Response Network

“…1E ). These findings support our previously published data suggesting that MET-DDR crosstalk is characteristic only for a particular subset of cancers with active MET receptor signaling ( 28 , 39 ).…”

A DNA-PK phosphorylation site on MET regulates its signaling interface with the DNA damage response

“…Recently, we have reported extensive descriptions of MET-dependent phosphoproteome in response to DNA damage [ 21 , 22 ]. In the present study, we explore one unexpected DNA damage-related phosphorylation site that we extracted from this data [ 21 ]: the previously unreported Serine 1016 on MET itself (MET S1016).…”