Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

Abstract

Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.

Fig. 1. Schematic diagram of the different signaling pathways involved in resistance to EGFR tyrosine kinase inhibitors (TKIs) driven by Protein Kinase C delta (PKCδ) and receptor tyrosine kinase recycling.

a PKCδ is a common mediator involved in EGFR TKI resistance. EGFR TKIs, like gefitinib, does not inhibit EGFR pY1173 and induce the formation of inactive EGFR heterodimers. The sustained pY1173 by EGFR heterodimer promotes the activation of PLCγ2 and PKCδ and downstream oncogenic signalling pathways. EGFR interacts with other RTKs, which are implicated in PKCδ and downstream oncogenic signalling pathway activation. b Increased pY374-PKCδ levels (regulated by the opposing actions of FER and PTPN14) increase the amount of RTKs on the cell surface. EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitor, Y tyrosine, p phosphorylation, PLCγ2 phospholipase γ2, PKCδ protein kinase Cδ, SHP2 Src-homology 2 domain-containing phosphatase 2, FER feline sarcoma-related, RAB5 Ras-associated binding protein 5, RTK receptor tyrosine kinase, CDCP1 CUB domain-containing protein 1.

Fig. 2. Schematic overview of the Hippo signalling pathway.

(Left) When Hippo signalling is off, YAP enters the nucleus, interacts with TEAD and recruits other factors to induce gene transcription. (Right) When Hippo signalling is on, YAP is phosphorylated by LATS1/2 on multiple sites, resulting in interaction with 14-3-3 and cytoplasmic retention; phosphorylation also leads to YAP poly-ubiquitination and degradation. TEAD does not bind with YAP and target gene transcription is suppressed. MST1/2 mammalian Ste20-like kinase 1/2, SAV Salvador non-catalytic scaffold protein, LATS1/2 large tumour suppressor 1/2, YAP Yes-associated protein, Mob1 Mps one binder kinase activator-like 1, TEAD TEA domain family member 1, ABL Abelson murine leukaemia viral oncogene, β-Trcp β-transducin repeat-containing protein, NF2 neurofibromin 2.

Fig. 3. Crosstalk among EGFR, other receptor tyrosine kinases, and YAP minimises the effect of EGFR TKIs.

EGFR mutations, via tyrosine phosphorylation, lead to the activation of the MAPK, AKT, STAT3 and other downstream oncogenic signalling pathways (i.e. NF-κB). SHP2 modulates signals of receptor tyrosine kinases at the level of Ras. IL-6 signals via receptor complexes, which contain gp130, and promotes STAT3 activation and nuclear translocation. gp130 associates with Src and triggers activation of YAP through phosphorylation on the tyrosine residue 357, independently of STAT3. FOXM1 is a direct transcriptional target induced by YAP. YAP/FOXM1 transcriptional programme up-regulates SAC components, AURKA/B (encoding Aurora kinase A and B) and Skp2. FOXM1, which is regulated by ALKBH5 and m⁶A, enhances the activation of HGF/MET (see also Fig. 1 and legend). EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitor, Y tyrosine, p phosphorylation, PLCγ2 phospholipase γ2, PKCδ protein kinase Cδ, SHP2 Src-homology 2 domain-containing phosphatase 2, FER feline sarcoma-related, RAB5 Ras-associated binding protein 5, RTK receptor tyrosine kinase, CDCP1 CUB domain-containing protein 1, YAP Yes-associated protein, IL-6 interleukin-6, ALKBH5 α-ketoglutamarate-dependent dioxygenase homologue 5, m⁶A N6-methyladenosine, CTGF connective tissue growth factor, SAC spindle assembly checkpoint, PLK1 polo-like kinase 1, KIF11 kinesin family member 11, BIRC5 baculoviral IAP repeat-containing 5.