Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma

• Main Authors: Siddharth Sheth, Douglas R. Farquhar, Travis P. Schrank, Wesley Stepp, Angela Mazul, Michele Hayward, Nicholas Lenze, Paul Little, Heejoon Jo, M. Ben Major, Bhishamjit S. Chera, Jose P. Zevallos, D. Neil Hayes
• Format: Article
• Language: English
• Published: Wiley 2021-08-01
• Series: Laryngoscope Investigative Otolaryngology
• Subjects: laryngeal squamous cell carcinoma; oxidative stress; radiation resistance
• Online Access: https://doi.org/10.1002/lio2.588

Abstract Objectives Patients with laryngeal squamous cell carcinoma (LSCC) often fail radiation therapy (RT), when received as monotherapy or in combination with other treatment modalities. Mechanisms for RT failure are poorly understood. We hypothesized that tumors failing RT would have increased rates of somatic mutations in genes associated with radiation resistance, particularly in genes associated with the NFE2L2 oxidative stress pathway. Using targeted exome sequencing on pretreated LSCC tumors, we retrospectively compared somatic mutation profile with clinical data and response to treatment. Methods Tumors were classified as either radiation‐resistant (RR) or radiation‐sensitive (RS). RR was defined as persistent or recurrent disease within 2 years of receiving full‐dose RT. Early stage (ES) LSCC was defined as Stage I or II tumors without lymph node involvement. Eight genes associated with radiation resistance were prioritized for analysis. RT‐qPCR was performed on five NFE2L2 pathway genes. Results Twenty LSCC tumors were included and classified as either RR (n = 8) or RS (n = 12). No differences in individual rates of somatic mutations by genes associated with radiation resistance were identified. Higher rates of total mutational burden (TMB) and increased alterations associated with the NFE2L2 pathway was observed in RR vs RS tumors (P < .05). In an analysis of only ES‐LSCC patients (RR, n = 3 and RS, n = 3), RR tumors had increased NFE2L2 somatic pathway mutations (P = .014) and increased NQO1 mRNA expression (P = .05). Conclusion Increased TMB and NFE2L2 pathway alterations were associated with radiation resistance in LSCC. NQO1 mRNA expression may serve as a biomarker for RT response in ES‐LSCC. Level of Evidence: II1.