A 68-year-old male with metastatic melanoma is being treated with vemurafenib. Three months into therapy, he develops a rapidly growing, dome-shaped nodule on his right forearm. Shave biopsy reveals a well-differentiated squamous cell carcinoma (SCC) with keratoacanthomatous features. He has two similar, smaller lesions on his left forearm.
Which of the following best explains the pathogenesis of this lesion?
A. Direct immunosuppression from BRAF inhibition
B. Paradoxical activation of the MAPK pathway in keratinocytes with wild-type BRAF
C. Loss of p53 tumor suppressor activity secondary to ultraviolet exposure
D. MEK inhibition leading to impaired cell-cycle arrest
E. Cross-resistance between BRAF and EGFR signaling pathways
Rationale:
Having a strong grasp on the pathomechanisms of various medications used in oncodermatology can help providers better understand the target and the potential side effect profile of these medications. In this scenario, the patient developed a keratoacanthoma-type SCC after initiating treatment with Vemurafenib, a BRAF inhibitor. SCC development is a well-documented adverse effect of this medication class.
Correct Answer: B. Paradoxical activation of the MAPK pathway in keratinocytes with wild-type BRAF
Paradoxical activation occurs because vemurafenib inhibits mutant BRAF in melanoma cells but permits dimerization and signaling through wild-type RAF isoforms in normal keratinocytes. This unintended signaling stimulates keratinocyte proliferation and tumor formation. The process is especially pronounced in patients with cumulative UV damage.
Co-administration of a MEK inhibitor (such as trametinib or cobimetinib) reduces this risk by blocking downstream MAPK signaling, thereby counteracting the paradoxical ERK activation induced by BRAF inhibition in wild-type cells.
Incorrect Answer Explanations:
A. Direct immunosuppression from BRAF inhibition
BRAF inhibitors are not significantly immunosuppressive. The rapid onset of SCCs is not related to impaired immune surveillance.
C. Loss of p53 tumor suppressor activity secondary to ultraviolet exposure
While UV-induced p53 mutations contribute to keratinocyte carcinogenesis, this mechanism does not explain the temporal relationship between BRAF inhibitor initiation and sudden onset of SCC in our patient.
D. MEK inhibition leading to impaired cell-cycle arrest
By blocking downstream signaling, MEK inhibitors mitigate the paradoxical ERK activation that drives SCC formation. MEK inhibition is protective and historically has been combined with BRAF inhibitors to limit this risk.
E. Cross-resistance between BRAF and EGFR signaling pathways
EGFR activation is a mechanism of resistance in some cancers but is not implicated in the pathogenesis of SCCs induced by BRAF inhibitors. This choice does not explain the development of the phenomenon observed in our patient.
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