Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma.
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.
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America; Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai, China.
Shang
S
Guo
Translational Research Laboratory, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Hector
H
Lopez-Marquez
Translational Research Laboratory, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Kenneth C
KC
Fan
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Edwin
E
Choy
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Gregory
G
Cote
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
David
D
Harmon
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
G Petur
GP
Nielsen
Department of Orthopaedics, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
Cao
C
Yang
Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University, Shanghai, China.
Changqing
C
Zhang
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Henry
H
Mankin
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Francis J
FJ
Hornicek
Translational Research Laboratory, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Darrell R
DR
Borger
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Zhenfeng
Z
Duan
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D008080:Liposarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D055815:Young Adult
D000970:Antineoplastic Agents; D002945:Cisplatin; D058534:Class I Phosphatidylinositol 3-Kinases; D004317:Doxorubicin; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C522973:PI103; C484760:PIK3CA protein, human