Abstract Acquired resistance to mTOR inhibition remains a major challenge in TSC2-mutant metastatic epithelioid angiomyolipoma (EAML). We report a 30-year-old woman with metastatic EAML harboring biallelic TSC2 mutations who achieved a complete response to everolimus but developed disease progression after 16 months. Tumor rebiopsy revealed persistent TSC2 mutations and acquired CDKN2A/B deletion, accompanied by increased Ki-67 and emergence of TFE-3 immunoreactivity and focal S-100 positivity.
