SOX2 transactivates NRF2 to promote carboplatin resistance in lung squamous cell carcinoma

Abstract

Lung squamous cell carcinoma (LUSC) remains a major therapeutic challenge because of its pronounced resistance to chemotherapy, particularly carboplatin. In this study, we investigate the role of SOX2, a lineage-survival oncogene, in mediating carboplatin resistance in LUSC. We demonstrate that SOX2 is highly expressed in LUSC and is significantly associated with poor prognosis. Our results show that SOX2 directly transactivates the expression of NRF2, a master regulator of cellular redox homeostasis, thereby increasing glutathione (GSH) synthesis and protecting cells from carboplatin-induced oxidative stress. Pharmacological or genetic inhibition of NRF2 effectively abrogates SOX2-mediated carboplatin resistance both in vitro and in vivo, resensitizing LUSC cells to chemotherapy. These findings highlight SOX2 as a critical redox regulator that modulates NRF2 signaling to promote carboplatin resistance in LUSC. The identification of the SOX2-NRF2 axis as a potential therapeutic target suggests that NRF2 inhibition may represent a promising strategy to overcome chemoresistance in LUSC.

1. Introduction

Lung squamous cell carcinoma (LUSC) accounts for approximately 20%–30% of non-small cell lung cancer (NSCLC) cases and collectively comprises approximately 80% of all lung cancers [1][2]. Since the 1990s, the incidence of LUSC has declined, largely due to the success of smoking cessation programs [3], in contrast to lung adenocarcinoma (LUAD), another predominant NSCLC subtype that has benefited from targeted therapies against specific genetic alterations [4]. Despite significant advances in cancer therapeutics, effective therapies specifically tailored to LUSC are lacking [5]. Most LUSC patients are diagnosed at an advanced stage, characterized by limited treatment options and high disease-related mortality [6]. Treatment typically involves platinum-based chemotherapy regimens, such as carboplatin-containing combinations. Recent therapeutic approaches include the use of EGFR monoclonal antibodies (e.g., necitumumab) [7] and immune checkpoint inhibitors (e.g., pembrolizumab, pislelizumab, sintilimab) [8–10]. Platinum-immunotherapy combinations have now become the standard first-line treatment for metastatic LUSC [6,11]. However, despite these advancements, durable responses and long-term survival benefits remain rare [12]. Therefore, understanding the mechanisms underlying chemoresistance in LUSC is critical for developing novel therapeutic strategies to overcome resistance and improve patient outcomes.

Lineage survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages where these genes contribute to normal development [13]. The transcription factor SOX2 is frequently subjected to genomic amplification on chromosome 3q26.33 in squamous cell carcinomas (SCCs) and is now recognized as a key driver oncogene that promotes tumorigenesis, proliferation, and invasion/metastasis [14,15]. Notably, SOX2 plays a crucial role in determining squamous cell fate across various cellular origins [16]. Additionally, SOX2, in cooperation with PKCι or ΔNp63α, drives tumorigenesis in LUSC [17,18]. Cancer stem cells (CSCs), a subset of tumor cells with self-renewal and differentiation capabilities, are widely acknowledged for their critical role in therapeutic resistance [19]. SOX2 is a key transcription factor that not only maintains stem cell properties but also confers drug resistance [19]. Elevated SOX2 expression has been shown to be correlated with both drug resistance and poor patient survival [20]. Consequently, targeting SOX2 represents an attractive therapeutic strategy for cancer treatment [21]. However, progress in the development of SOX2 inhibitors has been limited, largely because of the “undruggable” nature of SOX2 as a transcription factor. Despite its well-established role in cancer therapy resistance, the contribution of SOX2 to carboplatin resistance in lung squamous cell carcinoma (LUSC) remains poorly understood.