Background: Several non receptor tyrosine kinases (RTKs) activated by EGFR tyrosine kinase inhibitors (TKI) have been identified. Src family kinases (SFKs), FAK and STAT3 protein and mRNA levels are elevated after EGFR TKI, driving activation of YAP1, which, in turn, upregulates AXL, MET and CDCP1. Methods: A combination of genomic, biological, in vivo models, and clinical patient cohorts were performed. The efficacy of gefitinib or osimertinib with several inhibitors, including dasatinib and TPX-0005, was examined. Since only TPX-0005 abrogated Src, FAK, JAK2 and STAT3 activity, the assays were carried out with this drug. Nude mice bearing PC9 or H1975 cells were treated with osimertinib plus TPX-0005. Gene expression analysis was conducted in two cohorts (Cohort 1 and 2) of EGFR mutant NSCLC patients and was correlated with progression-free survival (PFS), overall survival (OS), and response. Results: An array of RTKs and non-RTKs were overexpressed before therapy and were not ablated with either gefitinib or osimertinib. TPX-0005 with an EGFR TKI abolishes AXL and CDCP1 mRNA expression. In addition, SFKs siRNA reduced YAP1 phosphorylation. AXL, CDCP1 and MET phosphorylation were diminished when YAP1 or SFKs were knocked-down. The combination of an EGFR TKI with TPX-0005 was synergistic in several EGFR mutant NSCLC cell lines. Osimertinib plus TPX-0005 caused tumor regression in PC9 and H1975 xenograft models. In Cohort 1, the Cox analysis showed CDCP1 as an independent prognostic factor for PFS (hazard ratio [HR] 1.79, p = 0.0407) and OS (HR 2.23, p = 0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs in both cohorts of patients. Conclusions: CDCP1 and AXL warn of an aberrant activation of SFKs, FAK, STAT3 and YAP1 pathways. A Phase I trial of EGFR TKI plus TPX-0005 in EGFR mutant NSCLC is desirable.