EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer

Abstract

Despite the success of treating EGFR mutant lung cancer patients with EGFR tyrosine kinase inhibitors (TKIs), all patients eventually acquire resistance to these therapies. Although various resistance mechanisms have been described, there are currently no FDA-approved therapies that target alternative mechanisms to treat lung tumors with acquired resistance to first-line EGFR TKI agents. Here we found that EPHA2 is overexpressed in EGFR TKI resistant tumor cells. Loss of EPHA2 reduced the viability of erlotinib resistant tumor cells harboring EGFRT790M mutations in vitro and inhibited tumor growth and progression in an inducible EGFRL858R+T790M mutant lung cancer model in vivo. Targeting EPHA2 in erlotinib resistant cells decreased S6K1-mediated phosphorylation of cell death agonist BAD, resulting in reduced tumor cell proliferation and increased apoptosis. Furthermore, pharmacologic inhibition of EPHA2 by the small molecule inhibitor, ALW-II-41-27, decreased both survival and proliferation of erlotinib resistant tumor cells and inhibited tumor growth in vivo. ALW-II-41-27 was also effective in decreasing viability of cells with acquired resistance to the third generation EGFR TKI, AZD9291. Collectively, these data define a role for EPHA2 in the maintenance of cell survival of TKI resistant, EGFR mutant lung cancer and indicate that EPHA2 may serve as a useful therapeutic target in TKI resistant tumors.

Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer

“…This observation was in line with recent findings obtained in other studies demonstrating that EphA2 overexpression is involved in the resistance to both EGFR tirosin-kinase inhibitors (TKI) such erlotinib (lung cancer) (17) and vemurafenib (melanoma) (50) and moAbs as trastuzumab (breast cancer) (51). Additionally the EphA2 blockade is proposed as a new strategy to restore the anti-EGFR sensitivity.…”

“…Notably adenocarcinoma EphA2 high tumor cells showed low expression levels both of Krt20 and Lgr5 along with an increased expression of Ascl2 suggesting that the EphA2 high cell population in tumors could represent a fraction of cells that underwent dedifferentiation and likely acquired CSC-like properties as supported by other studies in CRC, NSCLC and glioblastoma (17,39,40). We validated expression molecular results with the IHC analysis and we showed an overlap between EphB2+ cells and Lgr5+/Krt20− cells in normal mucosa.…”

“…Furthermore, two recent clinical studies on head and neck squamous cell carcinoma and CRC patients suggested a role for EphA2 in responsiveness to cetuximab-based targeted therapy (15,16). A preclinical study on lung cancer also defined a role for EphA2 in the maintenance of cell survival of tyrosine kinase (TKI)-resistant, EGFR-mutant cells and indicated that EphA2 may serve as a useful therapeutic target in TKI-resistant tumors (17). …”

Emerging and Diverse Functions of the EphA2 Noncanonical Pathway in Cancer Progression

“…31) Amato et al compared EGFR TKI-sensitive with EGFR TKI-resistant EGFR-mutant lung cancer cell lines and determined that EphA2 Ser-897 and Tyr-588 phosphorylation as well as total EphA2 expression were markedly increased in the resistant cells. 65) Notably, EphA2 levels were higher in post-relapse tumor sections than in TKI-pretreatment tumor sections from four patients with the EGFR mutation. As expected, EphA2 knockdown reduced the cell viability of resistant cells in vitro.…”

Long non-coding RNA BC087858 induces non-T790M mutation acquired resistance to EGFR-TKIs by activating PI3K/AKT and MEK/ERK pathways and EMT in non-small-cell lung cancer

“…EGFR-mutant NSCLC patients who benefited from EGFR-TKI eventually develop acquire resistance to these therapies [4, 19]. Although a number of studies revealed that a variety of mechanisms can stimulate acquired resistance to EGFR-TKI including secondary mutations within EGFR at position T790, mutation in EGFR effector proteins, small-cell lung cancer histologic transformation and upregulation of parallel receptor tyrosine kinases (e.g., MET, HER2 and AXL) [4], the mechanisms responsible for about 20–30% of cases of acquired resistance to EGFR-TKIs are still unknown.…”