Combination RSL3 Treatment Sensitizes Ferroptosis- and EGFR-Inhibition-Resistant HNSCCs to Cetuximab

Abstract

Head and neck squamous cell carcinomas (HNSCCs) are a type of cancer originating in the mucosal epithelium of the mouth, pharynx, and larynx, the sixth most common cancer in the world. However, there is no effective treatment for HNSCCs. More than 90% of HNSCCs overexpress epidermal growth factor receptors (EGFRs). Although small molecule inhibitors and monoclonal antibodies have been developed to target EGFRs, few EGFR-targeted therapeutics are approved for clinical use. Ferroptosis is a new kind of programmed death induced by the iron catalyzed excessive peroxidation of polyunsaturated fatty acids. A growing body of evidence suggests that ferroptosis plays a pivotal role in inhibiting the tumor process. However, whether and how ferroptosis-inducers (FINs) play roles in hindering HNSCCs are unclear. In this study, we analyzed the sensitivity of different HNSCCs to ferroptosis-inducers. We found that only tongue squamous cell carcinoma cells and laryngeal squamous cell carcinoma cells, but not nasopharyngeal carcinoma cells, actively respond to ferroptosis-inducers. The different sensitivities of HNSCC cells to ferroptosis induction may be attributed to the expression of KRAS and ferritin heavy chain (FTH1) since a high level of FTH1 is associated with the poor prognostic survival of HNSCCs, but knocked down FTH1 can promote HNSCC cell death. Excitingly, the ferroptosis-inducer RSL3 plays a synthetic role with EGFR monoclonal antibody Cetuximab to inhibit the survival of nasopharyngeal carcinoma cells (CNE-2), which are insensitive to both ferroptosis induction and EGFR inhibition due to a high level of FTH1 and a low level of EGFR, respectively. Our findings prove that FTH1 plays a vital role in ferroptosis resistance in HNSCCs and also provide clues to target HNSCCs resistant to ferroptosis induction and/or EGFR inhibition.

IGF2BP3 is an essential N6-methyladenosine biotarget for suppressing ferroptosis in lung adenocarcinoma cells

“…3 F). Because nuclear receptor coactivator 4 (NCOA4), SLC3A2, GPX4, ACSL3, and FTH1 were previously established to control ferroptosis in tumor cells [ [40] , [41] , [42] , [43] ], we focused on the role of IGF2BP3 in ferroptosis in the current study.

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Role of dysregulated ferroptosis‑related genes in cardiomyocyte ischemia‑reperfusion injury: Experimental verification and bioinformatics analysis

“…KEGG analysis revealed that the HIF-1 signaling pathway and NOD-like receptor signaling pathway To further clarify the mechanisms underlying ferroptosis activation in IRI, a PPI network of DEFRGs was constructed, and several hub genes were identified, of which HIF1A, EGFR, HMOX1, and ATF3 were validated experimentally in an in vitro A/R model. Previous studies showed that these critical genes participate in the regulation of ferroptosis (46)(47)(48)(49). Furthermore, the HIF1A/PTGS2 pathway aggravates ferroptosis and mediates myocardial injury and inflammation after coronary microembolization (50).…”

Identification of EGFR as an essential regulator in chondrocytes ferroptosis of osteoarthritis using bioinformatics, in vivo, and in vitro study

“…For instance, it was shown that QSOX1 inhibited EGFR signal activation by enhancing ubiquitination-mediated degradation of EGFR, leading to sorafenib induced ferroptosis of hepatocellular carcinoma cells [ 67 ]. The ferroptosis inducer RSL3 showed a synthetic role with EGFR inhibitor, Cetuximab, to exacerbate the ferroptosis of nasopharyngeal carcinoma cells [ 68 ]. However, no studies have investigated the role of EGFR in chondrocytes ferroptosis.…”