Combined treatment with cetuximab and STA9090 has synergistic anticancer effects on human non-small cell lung cancer

Abstract

Cetuximab (CET), a human murine chimeric IgG monoclonal antibody and an inhibitor of epidermal growth factor receptor (EGFR), has been shown to be effective in treating various types of cancer. However, its use is hindered by limitations such as resistance development, variability in patient response, side effects, and challenges in biomarker identification. Therefore, CET is often combined with other targeted therapies or chemotherapies to enhance its effectiveness. In this study, we investigate the anticancer effects and underlying mechanisms of the combination of CET, an EGFR inhibitor, and STA9090, an inhibitor of heat shock protein 90 (Hsp90), in both in vitro and in vivo models of non-small cell lung cancer (NSCLC). The results demonstrate significantly stronger effects on NSCLC cells in response to combination therapy than to treatment with either agent alone, indicating that the combination of CET and STA9090 has potential synergistic effects. Additionally, the combination therapy inhibits tumor growth in a xenograft nude mouse model more effectively than treatment with either agent alone, suggesting improved efficacy when used together. Furthermore, the synergistic effects of the combination therapy are likely due to inactivation of the receptor tyrosine kinase (RTK) pathway, which is overly activated in cancer and contributes to tumor growth, angiogenesis, and metastasis. Consequently, our findings suggest that STA9090 has potent direct antitumor activity and synergizes with CET against NSCLC tumors. It is highly likely that these synergistic effects are mediated through RTK pathway inactivation caused by the combination. Therefore, our findings strongly and consistently support the potential synergistic effect of STA9090, an RTK inhibitor, in combination with EGFR-targeting agents.

1. Introduction

Currently, lung cancer is the leading cause of cancer-related death and one of the most frequently diagnosed cancers worldwide [1,2]. According to statistics from GLOBOCAN, in 2020, lung cancer was the most commonly diagnosed cancer, accounting for 11.6% of the total cases, and was the leading cause of cancer death, accounting for 18.4% of all cancer deaths [3]. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases, with small cell lung cancers accounting for 15% of the total population [4–6]. The World Health Organization (WHO) classifies NSCLC into three major types: adenocarcinoma (approximately 38.5% of all lung cancer cases), squamous cell carcinoma (20% of all lung cancer cases) and large cell carcinoma (3%) [7,8]. Despite recent advances in early diagnosis and multimodal treatments such as surgery, chemotherapy and irradiation, lung cancer remains a serious global public health concern [9]. The historically poor median survival and low 5-year survival rate of patients with advanced NSCLC can be attributed to recurrence and metastasis [10]. Globally, the annual diagnosis rate of new cases is approximately 2.1 million, with five-year survival rates ranging from 4%–17% depending on the stage and region [11–13].

NSCLC is the most common form of lung cancer, and oncogenic activation of receptor tyrosine kinases (RTKs), such as EGFR, protein kinase B (PKB, also known as AKT), and extracellular regulated protein kinase (ERK), is especially relevant for this disease [14]. EGFR, a member of the ErbB family of RTKs, is often overexpressed or mutated in NSCLC, contributing to the pathogenesis of this disease [15]. Tyrosine kinase inhibitors (TKIs) targeting EGFR have been extensively used as first-line therapies for patients with metastatic and recurrent NSCLC. However, primarily susceptible patients eventually develop acquired drug resistance due to secondary EGFR mutations, T790M or activation of bypass signaling pathways to maintain persistent oncogenic EGFR signaling. Therefore, developing anticancer drugs that block multiple molecular targets involved in various oncogenic signaling pathways, rather than a single target in a single specific signaling pathway, is critical and could lead to effective therapeutic strategies.