Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Published: 9 November 2020| Version 1 | DOI: 10.17632/9nnzcvc89r.1
Radha Mukherjee


The PI3K pathway is mutated in a substantial set of tumors which includes alterations in PIK3CA and PTEN genes. However PI3K mutations often co-occur with other primary drivers like RAS, RAF, HER2. Also PI3K pathway inhibitors have not been successful in PI3K mutant tumors, attributed primarily to toxicity related issues and adaptive resistance contributed by relief of negative feedback mechanisms (induction of RTKs). Now we show that PTEN, the major negative regulator of PI3K signaling is regulated by the pathway by mTOR-4EBP1 dependent translation thereby constituting a feedback loop. We show that inhibition of PI3K signaling pharmacologically (eg PI3K inhibitors) or physiologically (amino acid or serum starvation) reduces PTEN and contributes to the resuscitation of the pathway and reduces the efficacy of the PI3K inhibitors. Physiological (ligands) or oncogenic stimulation of the pathway induces PTEN levels thereby regulating the duration and amplitude of signaling. Oncogenic induction of the pathway by PIK3CA activating mutations or HER2 overexpression induces the pathway to different degrees and mirrored by the levels in PTEN protein. Therefore PTEN levels maybe an indicator of PI3K pathway output and also serve to limit the output of PIK3CA mutants. We find that co-alterations in PIK3CA and PTEN increases PI3K and mTORC1 signaling greatly as compared to PIK3CA mutation alone, thereby creating a rationale for selection for co-mutations. Consistent with this hypothesis we find that a subset of tumors co-select for these mutations, especially endometrial cancers in which they co-occur in 70% of tumors. The mechanism of this phenomenon was found to be PI3K control of mTOR and its regulation of the cap-dependent translation inhibitor 4E-BP1. This mechanism was further confirmed by removing the 5'UTR of PTEN, conditions in which, PTEN protein was insensitive to PI3K dependent regulation and resulted in increased duration of pathway inhibition and increased efficacy of PI3K inhibitors. We have also built a computational model of the PI3K network consisting of the FOXO-RTK and 4E-BP1-PTEN feedback loops to quantitatively confirm the role of the 4E-BP1-PTEN feedback in determining the steady state and kinetic responses of PTEN and pAKT to PI3K inhibition in multiple cell lines. Overall, our investigation has identified a major homeostatic regulation of the PI3K network that involves regulation of the second most mutated tumor suppressor genes, PTEN, by one of the most mutated oncogenes PI3K. This has major implications for cancer therapy, understanding the biology of PI3K pathway driven tumors and mechanisms that drive homeostasis in the growth factor network.



Memorial Sloan Kettering Cancer Center


Cell Biology, Breast Cancer, Cancer Systems Biology