Targeting estrogen receptor and ERBB kinases in non-small cell lung cancer

Abstract

Lung cancer is the leading cause of cancer deaths worldwide with 5-year survival rate less than 20%. The most common subtype of lung cancer is non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers. Many epidemiological observations have linked estrogen signaling with worse lung cancer prognosis and poor survival. Previous reports have shown that estrogen can enhance the proliferation of lung cancer cells through activation of human epidermal growth factor receptor (EGFR/HER1) pathway by inducing their ligands release suggesting a functional interaction between the two pathways. However, it is still not clear whether other receptors and ligands within HER family are also involved in response to estrogen and how estrogen receptor and HER receptors modulate each other in lung cancer. Here, we showed that HER3 and HER2 were also activated upon short treatment with 17β-estradiol in a ligand-dependent manner. Estradiol treatment induced rapid and robust release of nuregulin-1 (NRG-1), the main ligand for HER3 receptor that upon binding initiates hetero-dimerization with other HER receptors, most likely HER2. Pharmacological inhibition of HER family with pan-HER tyrosine kinase inhibitor, dacomitinib, and estrogen receptors with fulvestrant showed an enhanced inhibitory effect against HER receptors and their downstream signaling. Interestingly, we observed that inhibiting either pathways led to upregulation of the other indicating a compensatory mechanism has taken place. Active NRG-1 and ampiregulin (AREG) as well as their mRNA expression were elevated with fulvestrant, and ERβ and aromatase mRNA expression were upregulated with dacomitinib. Dual therapy strongly suppressed c-Myc and Cyclin D1 and both drugs worked synergistically to inhibit cell growth and induce apoptosis across many NSCLC cell lines that harbor different driving mutations. We therefore have a substantial evidence for new combination therapy in NSCLC that worth further investigation in vivo models of lung cancer.