Therapeutic Vulnerabilities of the Key Genetic Drivers in Leiomyosarcoma

Leiomyosarcoma (LMS) is a rare, aggressive soft-tissue sarcoma arising from smooth muscle cells. It has a high metastatic potential and limited therapeutic options. Despite advances in oncology, the molecular landscape of LMS remains incompletely understood, particularly regarding the genetic and epigenetic alterations that affect key signaling pathways. This review summarizes the current knowledge of mechanisms driving LMS pathogenesis, including somatic mutations in genes such as TP53 and RB1, chromosomal instability, dysfunction of DNA damage response and repair, aberrant DNA methylation, histone modifications, and non-coding RNAs. Emerging treatment strategies include inhibitors of PI3K/AKT/mTOR and CDK4/6 signaling, epigenetic drugs, immunotherapy, and combinations of these approaches. However, the coexistence of multiple genetic abnormalities complicates diagnosis, prognosis, and therapeutic selection. Companion diagnostic tools that test candidate therapies ex vivo or in vitro may help exclude potentially ineffective targeted treatments.