FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR

Abstract

Human lung adenocarcinomas with activating mutations in EGFR (epidermal growth factor receptor) often respond to treatment with EGFRtyrosine kinase inhibitors(TKIs),butthe magnitude of tumour regression is variable and transient1,2. This heterogeneity in treatment response could result from genetic modifiers that regulate the degree to which tumour cells are dependent on mutant EGFR. Through a pooled RNA interference screen, we show that knockdown of FAS and several components of the NF-κB pathway specifically enhanced cell death induced by the EGFR TKI erlotinib in EGFR-mutant lung cancer cells. Activation of NF-κB through overexpression of c-FLIP or IKK (also known as CFLAR and IKBKB, respectively), or silencing of IκB (also known as NFKBIA), rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic or pharmacologic inhibition of NF-κB enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models. Increased expression of the NF-κB inhibitor IκB predicted for improved response and survival in EGFR-mutant lung cancer patients treated with EGFR TKI. These data identify NF-κB as a potential companion drug target, together with EGFR, in EGFR-mutant lung cancers and provide insight into the mechanisms by which tumour cells escape from oncogene dependence.

EGF receptor uses SOS1 to drive constitutive activation of NFκB in cancer cells

“…Constitutive NFκB activation contributes importantly to resistance to therapies in many cancers (1,41,42), and we show here that increasing NFκB activation by treating cells with IL-1β greatly increased resistance to erlotinib. We conclude that there is an important connection between EGFR and NFκB activation in cancer cells.…”

EGFR and NF-κB: partners in cancer

“…Consistent with a role of NF-kB in the resistance to EGFR inhibitors, the genetic or pharmacologic inhibition of NF-kB increased the sensitivity to erlotinib in several models of EGFR-mutated lung cancers. Moreover, decreased expression of the inhibitory IkBa protein is associated with resistance to erlotinib and is predictive of worse progression-free survival in patients suffering from lung cancer [49]. Consistent with a role of NF-kB as a mediator of resistance to EGFR inhibitors, quinacrine overcomes resistance to erlotinib, at least by decreasing the level of SSRP1, an active subunit of the Figure 3.…”

“…An unbiased screen for oncogenic pathways underlying resistance to EGFR inhibitors led to the identification of multiple candidates involved in NF-kB signaling [49]. Indeed, an unbiased short hairpin RNA (shRNA)-based high-throughput screen carried out in lung cancer-derived H1650 cells insensitive to EGFR inhibitors led to the identification of several candidates, many of which act in NF-kB-activating cascades [49].…”

“…Indeed, an unbiased short hairpin RNA (shRNA)-based high-throughput screen carried out in lung cancer-derived H1650 cells insensitive to EGFR inhibitors led to the identification of several candidates, many of which act in NF-kB-activating cascades [49]. Consistent with a role of NF-kB in the resistance to EGFR inhibitors, the genetic or pharmacologic inhibition of NF-kB increased the sensitivity to erlotinib in several models of EGFR-mutated lung cancers.…”

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

“…Filling this knowledge gap is critical, because the clinical success of driver oncogene-targeted therapies is limited by the almost inevitable escape from oncogene dependence and drug resistance that occur in patients with solid tumors, including lung cancer, the leading cause of cancer mortality worldwide (2,3). The identification of the signaling events driving resistance provides insights into the molecular mechanisms underlying oncogene dependence and a rationale for mechanism-based polytherapy strategies to subvert resistance in patients (2,4,5).…”