EGFR Signaling Through an Akt-SREBP-1–Dependent, Rapamycin-Resistant Pathway Sensitizes Glioblastomas to Antilipogenic Therapy

Abstract

Glioblastoma, the most common malignant brain tumor, is among the most lethal and difficult cancers to treat. Although epidermal growth factor receptor (EGFR) mutations are frequent in glioblastoma, their clinical relevance is poorly understood. Studies of tumors from patients treated with the EGFRinhibitor lapatinib revealed that EGFR induces the cleavage and nuclear translocation of the master transcriptional regulator of fatty acid synthesis, sterol regulatory element-binding protein 1 (SREBP-1). This response was mediated by Akt; however, clinical data from rapamycin-treated patients showed that SREBP-1 activation was independent of the mammalian target of rapamycin complex 1 (mTORC1), possibly explaining rapamycin's poor efficacy in the treatment of such tumors. Glioblastomas without constitutively active EGFR signaling were resistant to inhibition of

Lipogenesis in cancer progression (Review)

“…SREBP1 also increases reactive oxygen species (ROS) production (101) inducing tumor progression (102). A similar role of progesterone and EGF on SREBP cleavage and expression was reported in breast cancer cells (22,65,67).…”

“…High SCD1 expression is associated with cancer cell proliferation (18) and with a decrease in cell death (18)(19)(20)(21). SREBP1c also plays a role in the transformation of normal cells (22).…”

Identification of Akt-selective cytotoxic compounds that enhance cytotoxic responses to rapamycin

“…Because rapamycin has elicited mostly cytostatic effects in clinical chemotherapy, identifying mechanisms for enhancing the potential tumor-specific cytotoxic effects of rapamycin is an important problem. 10,17 The mixed results in the clinic may be due to inhibition of the negative feedback regulation of Akt, such that some tumors treated with rapamycin or its analogs display increased phosphorylation of Akt. 12 The UCDD compounds reduced Akt phosphorylation, possibly by interfering with upstream activating kinases.…”

“…10,11 Although rapamycin opposes survival signaling by Akt and mTORC1, rapamycin can also trigger a counter-productive increase in phosphorylation of Akt itself, potentially impairing cytotoxic chemotherapeutic responses to rapamycin in tumor cells. 10,12,17 Because UCDD001 and UCDD002 are cytotoxic for Akt-expressing cells, we sought to determine their efficacy in combination with rapamycin, an Akt-selective chemotherapeutic that has been approved for treatment of renal clear cell carcinoma. 9 At a concentration that is selectively cytotoxic for Akt-dependent cells, UCDD001 enhanced the cytotoxic effect of rapamycin in Akt-expressing cells (Fig.…”

Key Principles in Glioblastoma Therapy

“…Selective targeting of EGFR hyperactive glioblastomas can, thus, be achieved by inhibition of these repair process. Other groups have demonstrated that EGFR hyperactivation in glioblastoma cell lines heightens requirement for lipogenesis 30,31 . Other examples of such critical non-oncogenic pro-survival functions required for maintenance of the tumorigenic state include dependency on mechanism for compensating mitotic and proteotoxic stress and interplay with the tumor microenvironment including the immune system 26 .…”