Abstract 5174: Exploring extinction therapy for advanced cutaneous squamous cell carcinoma using UV-induced mouse models

Abstract Advanced cutaneous squamous cell carcinoma (cuSCC) remains a major therapeutic challenge, with an estimated 50.000 cases annually in the United States. While anti-PD1 immunotherapy—the only FDA-approved therapy—yields response rates of approximately 50%, responses to chemotherapy and radiotherapy are typically transient, and no comprehensive strategy for immunotherapy-refractory disease exists. We developed a novel K14-CreERT2 Confetti mouse model to investigate cuSCC progression, from UV-induced mutagenesis to invasive tumors. This model enables lineage tracing of keratinocytes and their progeny through fluorescent labeling, allowing precise monitoring of tumor evolution. Using this platform, we conducted a preclinical study across multiple tumor development stages to compare continuous therapy with extinction therapy—a novel first-strike-second-strike approach hypothesized to exploit vulnerabilities in fragmented cancer populations. Fifty-four mice were exposed to UV radiation on one side of their backs to induce mutagenesis, mimicking human cuSCC progression. The animals were divided into early-stage (tumors ∼3mm) and late-stage (tumors ∼6mm) cohorts based on tumor size at enrollment. Mice were assigned to either continuous or extinction therapy regimens, receiving combinations of anti-PD1 immunotherapy and the MEK inhibitor trametinib. Continuous therapy involved initial treatment with either immunotherapy or targeted therapy until the tumor grew 20% larger than its enrollment size. Then, the therapy switched to the alternate modality and continued until the endpoint (tumors >10mm). Extinction therapy began with either targeted therapy or immunotherapy, with treatments alternating under specific conditions: when tumors failed to respond after two weeks or when a different tumor exceeded the initial tumor’s enrollment size. This adaptive strategy aimed to enhance efficacy by targeting dynamic tumor vulnerabilities. UV-irradiated versus non-irradiated skin was monitored through confocal microscopy for eight months post-irradiation to evaluate resistance evolution and underlying cellular and clonal changes. As observed previously, tumors only developed on UV-irradiated skin, with significant variability in tumor numbers (3-25 per animal). Tumor burden was assessed twice weekly to evaluate therapy efficacy. Preliminary results suggest that extinction therapy significantly reduced tumor burden and delayed resistance compared to continuous treatment, particularly in advanced disease stages. We provide valuable insights into therapeutic strategies for cuSCC management with our approximation of treatment regimen combinations and their efficacy across distinct tumor progression stages. Citation Format: Karol M. Prieto-Sarmiento, Stanislav Avdieiev, Omar Chavez Chiang, Sofia Cordero, Irmak Aksit, Derek Weimer, Christopher J. Whelan, Joel S. Brown, Kenneth Y. Tsai. Exploring extinction therapy for advanced cutaneous squamous cell carcinoma using UV-induced mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5174.