Inhibition of the mechanistic target of rapamycin induces cell survival via MAPK in tuberous sclerosis complex

Abstract

Background: Tuberous sclerosis complex (TSC) is a genetic disorder that cause tumors to form in many organs. These lesions may lead to epilepsy, autism, developmental delay, renal, and pulmonary failure. Loss of function mutations in TSC1 and TSC2 genes by aberrant activation of the mechanistic target of rapamycin (mTORC1) signaling pathway are the known causes of TSC. Therefore, targeting mTORC1 becomes a most available therapeutic strategy for TSC. Although mTORC1 inhibitor rapamycin and Rapalogs have demonstrated exciting results in the recent clinical trials, however, tumors rebound and upon the discontinuation of the mTORC1 inhibition. Thus, understanding the underlying molecular mechanisms responsible for rapamycin-induced cell survival becomes an urgent need. Identification of additional molecular targets and development more effective remission-inducing therapeutic strategies are necessary for TSC patients. Results: We have discovered an Mitogen-activated protein kinase (MAPK)-evoked positive feedback loop that dampens the efficacy of mTORC1 inhibition. Mechanistically, mTORC1 inhibition increased MEK1-dependent activation of MAPK in TSC-deficient cells. Pharmacological inhibition of MAPK abrogated this feedback loop activation. Importantly, the combinatorial inhibition of mTORC1 and MAPK induces the death of TSC2-deficient cells. Conclusions: Our results provide a rationale for dual targeting of mTORC1 and MAPK pathways in TSC and other mTORC1 hyperactive neoplasm.

Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling

“…We utilized the liver-specific Kras G12D activating mutation (herein referred to as KC or Kras G12D ;Alb-Cre mice) to establish constitutively active Kras G12D mutation in C57BL/6 mice. Loss of either Tsc1 or Tsc2 decreases the inhibition of mTOR, leading to its activation 27 . Hence, liver-specific Tsc1-knockout mice (herein referred to as TC or Tsc1 fl/fl ;Alb-Cre mice) were also generated.…”

MAPK13 stabilization via m6A mRNA modification limits anticancer efficacy of rapamycin

“…Some of these progrowth signals such as PI3K and RAS are upstream activators of mTORC1; therefore, when mTORC1 is suppressed by rapamycin, these negative feedbacks are released, resulting in the continued growth of cancer cells ( 59 ). On the other hand, cotreatment of rapamycin with PI3K or MEK inhibitors is more effective for tumor suppression in cell culture and mouse models ( 58 , 60 ). Here, we identified MAPK13 as a target gene regulated by mTORC1-dependent m 6 A regulation and as another key factor that potentially limits rapamycin’s tumor-suppressive effects.…”

MAPK13 stabilization via m6A modification limits anti-cancer efficacy of rapamycin

“…Some of these pro-growth signals such as PI3K and RAS are upstream activators of mTORC1; therefore, when mTORC1 is suppressed by rapamycin, these negative feedbacks are released, resulting in the continued growth of cancer cells (34). On the other hand, cotreatment rapamycin with PI3K or MEK inhibitors is more effective for tumor suppression in cell culture and mouse models (33,35). Here, we identified MAPK13 as another player that (which was not certified by peer review) is the author/funder.…”