Insulin-like growth factor 2 axis supports the serum-independent growth of malignant rhabdoid tumor and is activated by microenvironment stress

Malignant rhabdoid tumors (MRTs) are rare, lethal, pediatric tumors predominantly found in the kidney, brain and soft tissues. MRTs are driven by loss of tumor suppressor SNF5/INI1/SMARCB1/BAF47. The prognosis of MRT is poor using currently available treatments, so new treatment targets need to be identified to expand treatment options for patients experiencing chemotherapy resistance. The growth hormone insulin-like growth factor 2 (IGF2) signaling pathway is a promising target to overcome drug resistance in many cancers. Here, we evaluated the role of IGF2 axis in MRT cell proliferation. We showed that microenvironment stress, including starvation treatment and chemotherapy exposure, lead to elevated expression of IGF2 in the SNF5-deficient MRT cell line. The autocrine IGF2, in turn, activated insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), followed by PI3K/AKT pathway and RAS/ERK pathway to promote cancer cell proliferation and survival. We further demonstrated that impairment of IGF2 signaling by IGF2 neutralizing antibody, IGF1R inhibitor NVP-AEW541 or AKT inhibitor MK-2206 2HCl treatment prevented MRT cell growth in vitro. Taken together, our characterization of this axis defines a novel mechanism for MRT cell growth in the microenvironment of stress. Our results also demonstrated the necessity to test the treatment effect targeting this axis in future research.