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Who's Driving? Switch of Drivers in Immunotherapy-Treated Progressing Sinonasal Melanoma
Sandra N Freiberger1,2, Patrick Turko3, Martin Hüllner2,4
1Department of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland.
Abstract:
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.
Insights
Metastatic sinonasal melanoma can switch oncogenic drivers, particularly to NRAS, during immunotherapy, leading to disease progression. Longitudinal molecular testing is crucial for detecting this unforeseen event and guiding treatment strategies.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Mucosal melanoma is driven by mutations in genes like NRAS, KIT, or KRAS.
- Some cases lack clear drivers, favoring immunotherapy over targeted therapy.
- Resistance to immunotherapy in cutaneous melanoma is known, but driver switching is unobserved.
Purpose of the Study:
- To investigate the phenomenon of oncogenic driver switching in metastatic sinonasal melanoma under immunotherapy.
- To identify potential molecular mechanisms associated with treatment resistance and disease progression.
Main Methods:
- Retrospective analysis of three metastatic sinonasal melanoma cases treated with immunotherapy.
- Molecular profiling of primary tumors and subsequent lesions to detect changes in driver mutations.
- Comparison with three control cases treated with radiotherapy only.
Main Results:
- Three patients exhibited a switch in oncogenic drivers from KRAS, KIT, or no driver to NRAS during or after immunotherapy.
- This driver switch correlated with progressive disease.
- One case showed multiple primary driver mutations, with NRAS persisting under immunotherapy, unlike radiotherapy-treated controls.
Conclusions:
- A switch to NRAS as the dominant oncogenic driver can occur in sinonasal melanoma during immunotherapy.
- Longitudinal molecular testing is recommended to detect emerging NRAS clones and guide treatment.
- Further research is warranted to explore the causal relationship between NRAS clone emergence and immunotherapy response.
