PCC0208027, a novel tyrosine kinase inhibitor, inhibits tumor growth of NSCLC by targeting EGFR and HER2 aberrations

Qiuju Dong,Pengfei Yu,Hiroshi Kurihara,Fangxia Zou,Liang Ye,Hongbo Wang,Jianzhao Zhang,Jingwei Tian

doi:10.1038/s41598-019-42245-3

Abstract

PCC-0208027 is a novel tyrosine kinase inhibitor that has a strong inhibitory effect on epidermal growth factor receptor (EGFR)- or HER2-driven cancers. The aim is to assess the anti-tumor activity of PCC0208027 and related mechanisms in non-small cell lung cancer (NSCLC). We examined the activity of PCC0208027 on various mutated EGFRs, HER2, and HER4. MTT assays, flow cytometry, and Western blotting were used to examine the effects of PCC0208027 on NSCLC cells with different genetic characteristics and relevant molecular mechanisms. Nude mouse xenograft models with HCC827, NCI-H1975, and Calu-3 cells were used to evaluate the in vivo anti-tumor activity of PCC0208027. Results showed that PCC0208027 effectively inhibited the enzyme activity of EGFR family members, including drug-sensitive EGFR mutations, acquired drug-resistant EGFR T790M and EGFR C797S mutations, and wild-type (WT) HER2. PCC0208027 blocked EGFR phosphorylation, thereby downregulating downstream PI3K/AKT and MAPK/ERK signaling pathways and inducing G0/G1 arrest in NSCLC cells. PCC0208027 inhibited tumor growth in mouse xenograft models of HCC827, NCI-H1975, and Calu-3 cells. In summary, our findings suggest that PCC0208027 has the potential to become an oral antineoplastic drug for NSCLC treatment and is worthy of further development.

Highlights

Lung cancer is one of the most common cancers and is currently the leading cause of cancer-related deaths
Osimertinib, a next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), is approved in the US for the treatment of patients with EGFR T790M mutation-positive inoperable or recurrent non-small cell lung cancer (NSCLC) that is resistant to EGFR TKI therapy, and for the first-line treatment of patients with inoperable or recurrent EGFR mutation-positive NSCLC
PCC0208027 demonstrated a comparable inhibitory effect on EGFR T790M mutation as osimertinib, and a strong inhibitory effect on the EGFR C797S mutation, which was resistant to osimertinib

Summary

Introduction

Lung cancer is one of the most common cancers and is currently the leading cause of cancer-related deaths. Small molecule EGFR tyrosine kinase inhibitors (TKIs) have become the mainstay targeted therapy for NSCLC patients with EGFR mutations[3,5,6]. Gefitinib, and afatinib are first-line treatments for NSCLC patients with EGFR exon 19 deletion or exon 21 L858R mutations. HER2 amplification is one of the mechanisms by which patients develop secondary drug resistance to EGFR TKIs17. We systematically evaluated the anti-tumor activity of PCC0208027 in NSCLC tumors with drug-sensitive or -resistant EGFR mutations, and HER2 amplification, and elucidated its potential anti-tumor mechanisms. This will provide more potential EGFR TKI options for NSCLC treatment

Methods

Results

Conclusion