Abstract 4998: Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation

• Published in: Cancer research (Chicago, Ill.) Vol. 84; no. 6_Supplement; p. 4998
• Main Authors: Yoon, Shinkyo, Ryu, Hyun-Min, Kim, Sang-We, Park, Kang-Seo, Lee, Dae Ho
• Format: Journal Article
• Language: English
• Published: 22.03.2024
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2024-4998

Abstract Background: Oncogenic alteration in RET, representing 1-2% of non-small cell lung cancer (NSCLC), is one of the important targets. Pralsetinib is a selective RET inhibitor that targets RET fusions. We present a case series on opportunistic infections and the mechanism of immunosuppression. Methods: From October 2021 to March 2022, we administered pralsetinib to a total of 15 patients with NSCLC harboring RET fusion. We retrospectively analyzed the clinical efficacy and adverse event related to pralsetinib. To investigate the potential impact of pralsetinib on T-cells, we examined cytokine release from Jurkat T (JT) cells after pralsetinib treatment. To test if Stat5 bind to IL-2 promotor, we conducted Chromatin Immunoprecipitation (ChIP). Results: Out of a total of 18 patients with measurable disease, 14 patients (93%) achieved a partial response. With the median follow-up duration of 8.7 months, four cases of opportunistic infections were occurred. Notably, three patients (16.6%) experienced invasive pulmonary aspergillosis, and one patient (5.5%) experienced cytomegalovirus pneumonia. To mimic conditions akin to activated T cells, we treated JT cells with PMA and ionomycin, inducing IL-2 release through the binding of NFAT, AP-1, and NF-κB to the IL-2 promoter. Following approximately two weeks of pralsetinib treatment, a decrease of IL-2 releases, the inhibition of Jak3 and the reduced-expression of JunB and c-Jun was observed. Additionally, to investigate the direct correlation between Jak3 and IL-2 release, JT cells were treated with ritlecitinib, the Jak3-selective inhibitor, for approximately two weeks. Like pralsetinib, a reduction in IL-2 release was observed. Furthermore, based on the evidence that Stat5 inhibition leads to reduced IL-2 release, we also showed that the transcription factor Stat5, a direct downstream signaling component of Jak3, binds to the IL-2 promoter during the activation of Jurkat T cells. Conclusion: Pralsetinib inhibits additional IL-2 production by blocking Jak3/Stat5 activation triggered by IL-2 released during early T cell activation. As a result, the Jak3 inhibition induced by pralsetinib leads to a decrease in JunB/c-Jun expression and blocking Stat5 activation by reducing IL-2 release. Consequently, Pralsetinib-related opportunistic infections may be caused by inhibition of the JAK3 pathway and IL-2 release. Citation Format: Shinkyo Yoon, Hyun-Min Ryu, Sang-We Kim, Kang-Seo Park, Dae Ho Lee. Pralsetinib induces opportunistic infection in RET fusion-positive NSCLC patients via inhibition of IL-2 production by blocking Jak3-Stat5 activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4998.