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

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.

Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents

“…A higher hydrophobic contribution was found, due to a more deeply located binding pose inside the ATP binding site with respect to that observed in the wild type Erlotinib-EGFR complex. This contribution determined an increase of binding affinity and suggested an increasing Erlotinib inhibitory activity in presence of ELREA EGFR receptor, in agreement with experiment observations [33][34][35][36][37][38]. MD simulation trajectories revealed that this complex is very stable ( Figure S5) as confirmed by MM/PBSA binding energy values ( Figure 6).…”

“…The results showed very good stability for the complexes of Erl and EGCG with wild type and ELREA deletion EGFR forms. In line with experimental data, it is well established the ability of Erlotinib to target TK of EGFR-ELREA [32], yet a significant benefit of Erl treatments was found also in patients with EGFR-wild type [33,34]. In addition, EGCG shows high growth inhibition activity towards EGFR-wt and ELREA harboring NLSC cell lines [35].…”

Targeting Autophagy for Overcoming Resistance to Anti-EGFR Treatments

“…Constitutive signaling from the EGFR promotes cell survival, proliferation [1], and invasiveness [2]. Aberrant EGFR signaling has been found in many human malignancies, including colorectal, lung, breast, and head and neck cancer [3,4]. Overexpression and activating mutations of EGFRs reported in up to 30% of solid tumors (including breast, colorectal, lung, pancreatic, gastric, head and neck cancer, and glioblastomas) generally correlate with a poor prognosis [5,6].…”

Current Strategies for Treating NSCLC: From Biological Mechanisms to Clinical Treatment

“…This represents a new molecular targeted combination therapy for NSCLC patients with HER2 aberrations. Other HER target inhibitors, such as neratinib and PCC0208027, are also under-investigated, and further studies may provide more opportunities for treatment [ 52 , 53 ].…”