Synergistic Effects of Targeted PI3K Signaling Inhibition and Chemotherapy in Liposarcoma

Abstract

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.

Phosphatidylinositol-3-kinase (PI3K)/Akt Signaling is Functionally Essential in Myxoid Liposarcoma

“…Overall, previously published results indicate a fundamental relevance of PI3K/Akt signals with respect to the specific liability of MLS tumor cells, accomplished either by genetic PIK3CA and/or PTEN alterations or complex signaling networks (8,12,(15)(16)(17)22) resulting in aberrant activation of PI3K activity. This preclinical study was conducted to explore the functional importance of PI3K/ Akt signals in MLS tumorigenesis, and to establish a molecularly targeted strategy employing small-molecule PI3K inhibitors.…”

Hsp90 inhibition by AUY922 as an effective treatment strategy against myxoid liposarcoma

“…Moreover, AKT inactivation might lead to an increase in the anti-proliferative effect of the cell cycle inhibitor p21 that is normally held by AKT in the cytoplasm [29]. In general, the PI3K/AKT survival pathway is crucial for the survival of many soft tissue tumor subtypes [11,31,32].…”

“…MLS have an oncogenic activation of the PI3K pathway through mutations in the PIK3CA gene [32]. Only 10-15% of the MLS have this mutation and none of MLS402-91 or MLS1754-92 have these mutations [26].…”

Phosphatidylinositol 3-kinase/Akt signaling as a key mediator of tumor cell responsiveness to radiation

“…This latter statement is supported by the increased cytotoxicity observed in tumor cells of different origins to chemotherapy agents such as microtubule-targeting drugs (paclitaxel, docetaxel and vinblastine) [115], topotecan [116], cisplatin [117], and doxorubicin [118], when treatment was combined with inhibitors of components of PI3K/Akt pathway. Likewise, early evidence of antitumor activity, induced by either inhibiting Akt using MK-2206 [119] plus carboplatin and paclitaxel, docetaxel, or erlotinib, or inhibiting PI3K using the pan-class 1A PI3K inhibitor BKM120 [120] plus carboplatin and paclitaxel in patients with different solid tumors, supports the above-described role for PI3K/Akt in resistance to chemotherapy agents [119,120].…”