| Autor: |
Landers SM; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bhalla AD; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ma X; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lusby K; Department of Surgery, Division of Plastic Surgery, Indianapolis University School of Medicine, Indianapolis, IN, USA., Ingram D; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Al Sannaa G; Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston TX, USA., Wang WL; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lazar AJ; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Torres KE; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. |
| Abstrakt: |
Dysregulation of the receptor tyrosine kinase AXL is known to promote cancer cell growth and survival in many sarcomas, including the rare subtype, malignant peripheral nerve sheath tumors (MPNST). MPNSTs are largely chemoresistant and carry a poor prognosis. AXL is an attractive potential therapeutic target, as it is aberrantly expressed, and its activation may be an early event in MPNST. However, the effect of AXL inhibition on MPNST development and progression is not known. Here, we investigated the role of AXL in MPNST development and the effects of AXL and MEK1/2 co-inhibition on MPNSTs. We used western blotting to examine AXL expression and activation in MPNST cell lines. We analyzed the effects of exogenous growth arrest-specific 6 (GAS6) expression on downstream signaling and the proliferation, migration, and invasion of MPNST cells. The effect of AXL knockdown with or without mitogen-activated protein kinase (MAPK) inhibition on downstream signal transduction and tumorigenesis was also examined in vivo and in vitro . We found that AXL knockdown increased MAPK pathway signaling. This compensation, in turn, abrogated the antitumorigenic effects linked to AXL knockdown in vivo . AXL knockdown, combined with pharmacological MEK inhibition, reduced the proliferation and increased the apoptosis of MPNST cells both in vitro and in vivo . The pharmacological co-inhibition of AXL and MEK1/2 reduced MPNST volumes. Together these findings suggest that AXL inhibition enhances the sensitivity of MPNST to other small molecule inhibitors. We conclude that combination therapy with AXL inhibitor may be a therapeutic option for MPNST. |
