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Article

Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma

1
Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland
2
Faculty of Medicine, University of Zurich, 8006 Zurich, Switzerland
3
Department of Dermatology, University Hospital Zurich, 8058 Zurich, Switzerland
4
Department of Nuclear Medicine, University Hospital Zurich, 8091 Zurich, Switzerland
5
Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, 8091 Zurich, Switzerland
6
Department of Otolaryngology, Head and Neck Surgery, Sir Mortimer B. Davis—Jewish General Hospital, McGill University, Montreal, QC H3T1E2, Canada
*
Author to whom correspondence should be addressed.
These authors contributed equally to the study.
Academic Editors: Mario Hermsen, Paolo Bossi, Alessandro Franchi and Matt Lechner
Cancers 2021, 13(11), 2725; https://doi.org/10.3390/cancers13112725
Received: 30 March 2021 / Revised: 12 May 2021 / Accepted: 28 May 2021 / Published: 31 May 2021
Here, we monitored the course of the disease and treatment of sinonasal melanoma patients. Since treatment options are rare, immunotherapy is often the treatment of choice. However, intrinsic or acquired resistance to treatment may occur. We assessed the mutational status of the tumors and metastases during the course of therapy and recognized a switch of the oncogenic drivers to mutant NRAS in progressing disease. As a switch of drivers (other than the addition of a second driver) has not been reported yet, longitudinal molecular testing and the awareness of molecular heterogeneity of sinonasal melanoma is crucial.
Mucosal melanoma can be driven by various driver mutations in genes such as NRAS, KIT, or KRAS. However, some cases present with only weak drivers, or lacking known oncogenic drivers, suggesting immunotherapy over targeted therapy. While resistance mechanisms to immunotherapy in cutaneous melanoma have been uncovered, including alterations in JAK1/2, B2M, or STK11, a switch of oncogenic drivers under immunotherapy has not yet been observed. We report three cases of metastatic sinonasal melanoma that switched oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy, thereby showing progressive disease. One of the cases presented with three spatially separate driver mutations in the primary tumor, whereas the NRAS clone persisted under immunotherapy. In comparison, three different control cases receiving radiotherapy only did not show a change of the detectable molecular drivers in their respective recurrences or metastases. In summary, these data provide an important rationale for longitudinal molecular testing, based on evidence for an unforeseen recurrent event of molecular driver switch to NRAS in progressing sinonasal melanoma. These findings provide the basis for further studies on a potential causal relation of emerging NRAS mutant clones and immunotherapy. View Full-Text
Keywords: mucosal melanoma; sinonasal cancer; oncogenic driver; immunotherapy; tumor heterogeneity; disease monitoring mucosal melanoma; sinonasal cancer; oncogenic driver; immunotherapy; tumor heterogeneity; disease monitoring
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MDPI and ACS Style

Freiberger, S.N.; Turko, P.; Hüllner, M.; Dummer, R.; Morand, G.B.; Levesque, M.P.; Holzmann, D.; Rupp, N.J. Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma. Cancers 2021, 13, 2725. https://doi.org/10.3390/cancers13112725

AMA Style

Freiberger SN, Turko P, Hüllner M, Dummer R, Morand GB, Levesque MP, Holzmann D, Rupp NJ. Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma. Cancers. 2021; 13(11):2725. https://doi.org/10.3390/cancers13112725

Chicago/Turabian Style

Freiberger, Sandra N., Patrick Turko, Martin Hüllner, Reinhard Dummer, Grégoire B. Morand, Mitchell P. Levesque, David Holzmann, and Niels J. Rupp 2021. "Who’s Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma" Cancers 13, no. 11: 2725. https://doi.org/10.3390/cancers13112725

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