NF-κB-Activating Complex Engaged in Response to EGFR Oncogene Inhibition Drives Tumor Cell Survival and Residual Disease in Lung Cancer

Abstract

Summary Although oncogene-targeted therapy often elicits profound initial tumor responses in patients, responses are generally incomplete because some tumor cells survive initial therapy as residual disease that enables eventual acquired resistance. The mechanisms underlying tumor cell adaptation and survival during initial therapy are incompletely understood. Here, through the study of EGFR-mutant lung adenocarcinoma we show that NF-κB signaling is rapidly engaged upon initial EGFR inhibitor treatment to promote tumor cell survival and residual disease. EGFR oncogene inhibition induced an EGFR-TRAF2-RIP1-IKK complex that stimulated an NF-κB-mediated transcriptional survival program. The direct NF-κB inhibitor PBS-1086 suppressed this adaptive survival program and increased the magnitude and duration of initial EGFR inhibitor response in multiple NSCLC models, including a patient-derived xenograft. These findings unveil NF-κB activation as a critical adaptive survival mechanism engaged by EGFR oncogene inhibition and provide rationale for EGFR and NF-κB co-inhibition to eliminate residual disease and enhance patient responses.

Inhibition of Casein Kinase 1 Alpha Prevents Acquired Drug Resistance to Erlotinib in EGFR-Mutant Non–Small Cell Lung Cancer

“…Accordingly, it has been described previously that the extent of NF-kB activity may determine the response to EGFR TKI treatment in patients with EGFR-mutant lung cancer, with low IkB expression, an indicator of high NF-kB activation, being predictive of worse progression-free survival and decreased overall survival of patients with EGFR-mutant lung cancer treated with erlotinib (18). Furthermore, adaptive NF-kB activation has recently been shown to enable survival of NSCLC cells upon initial EGFRtargeted therapy, thereby allowing tumor cell persistence manifesting as an incomplete tumor response that may ultimately promote acquired resistance (19).…”

“…Alternatively, key downstream signaling pathways can be reactivated through mechanisms independent of the original target, for example, through mutational activation of components of the PI3K/AKT and MEK/ERK pathways or through activation of bypass RTKs, such as MET (8)(9)(10), ErbB2 (11), IGF1R (12)(13)(14), FGFR1 (15), or AXL (16,17). Furthermore, activation of alternative pathways, such as upregulation of the prosurvival NF-kB signaling pathway, as well as a switch from epithelial-to-mesenchymal cell morphology (EMT) have been connected to both intrinsic and acquired resistance to EGFR TKIs (16,18,19).…”

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

“…To address this hypothesis, we used an established acquired resistance assay (4,37,38) in representative LA cell lines from our panel that express either V600E or non-V600 mutant forms of BRAF. Using HCC364 (BRAF V600E ) cells, we found that cotreatment with either erlotinib or everolimus (at concentrations that suppress signaling; Fig.…”

Epithelial NF-κB signaling promotes EGFR-driven lung carcinogenesis via macrophage recruitment

“…15,17 More recently, NF-kB activation was shown to drive resistance to a mutant-selective EGFR inhibitor in T790M mutant cells. 16 While these prior studies indicate that NF-kB signaling supports resistance of EGFR-mutant tumors to TKIs, our findings indicate that NF-kB signaling plays a broader role in EGFR-driven lung carcinogenesis.…”

“…[9][10][11][12] EGFR signaling is known to activate NF-kB in a variety of tumor types, 13,14 and NF-kB signaling has been shown to facilitate resistance to EGFR inhibitor therapies in lung cancer. [15][16][17][18] However, the importance of the NF-kB pathway during oncogenic EGFR-driven lung tumorigenesis has not been examined.…”