While
liposarcoma is the second most common soft tissue malignant
tumor, the molecular pathogenesis in this
malignancy is poorly understood. Our goal was therefore to expand the understanding of molecular mechanisms that drive
liposarcoma and identify therapeutically-susceptible genetic alterations. We studied a cohort of high-grade
liposarcomas and benign
lipomas across multiple disease sites, as well as two
liposarcoma cell lines, using multiplexed mutational analysis.
Nucleic acids extracted from diagnostic patient tissue were simultaneously interrogated for 150 common mutations across 15 essential cancer genes using a clinically-validated platform for
cancer genotyping. Western blot analysis was implemented to detect activation of downstream pathways.
Liposarcoma cell lines were used to determine the effects of PI3K targeted
drug treatment with or without
chemotherapy. We identified mutations in the PIK3CA gene in 4 of 18 human
liposarcoma patients (22%). No PIK3CA mutations were identified in benign
lipomas. Western blot analysis confirmed downstream activation of AKT in both PIK3CA mutant and non-mutant
liposarcoma samples.
PI-103, a dual PI3K/mTOR inhibitor, effectively inhibited the activation of the PI3K/AKT in
liposarcoma cell lines and induced apoptosis. Importantly, combination with
PI-103 treatment strongly synergized the growth-inhibitory effects of the
chemotherapy drugs
doxorubicin and
cisplatin in
liposarcoma cells. Taken together, these findings suggest that activation of the PI3K/AKT pathway is an important
cancer mechanism in
liposarcoma. Targeting the PI3K/AKT/pathway with small molecule inhibitors in combination with
chemotherapy could be exploited as a novel strategy in the treatment of
liposarcoma.