Question 1

What does mTOR do?

Accepted Answer

mTOR is a serine/threonine kinase that forms two distinct complexes: mTORC1 drives protein synthesis (via S6K1 and 4EBP1), ribosome biogenesis, and lipid synthesis while suppressing autophagy; mTORC2 phosphorylates and activates AKT at Ser473 and regulates cytoskeletal organisation.

Question 2

What cancers respond to mTOR inhibitors?

Accepted Answer

Everolimus (mTORC1 inhibitor) is approved for advanced renal cell carcinoma, HR+ breast cancer, and pancreatic neuroendocrine tumours. However, mTORC1 inhibition relieves S6K-IRS1 negative feedback, causing compensatory AKT activation — a key resistance mechanism that dual PI3K/mTOR inhibitors aim to overcome.

Question 3

What is tuberous sclerosis and mTOR?

Accepted Answer

Tuberous sclerosis complex (TSC) is caused by germline mutations in TSC1 or TSC2, which encode the hamartin-tuberin complex that acts as a GAP for the small GTPase RHEB. Loss of TSC1/TSC2 causes constitutive RHEB-mediated mTORC1 activation, driving benign hamartoma growth in kidney, brain, lung, and skin.

Question 4

Why do mTOR inhibitors paradoxically activate AKT?

Accepted Answer

When mTORC1 is inhibited by rapalogs (everolimus, temsirolimus), active S6K1 is suppressed. S6K1 normally phosphorylates IRS-1 at inhibitory serine residues, reducing IRS-1's ability to activate PI3K downstream of insulin and IGF1 receptors. When S6K1 is suppressed, IRS-1 dephosphorylation restores its activating function, leading to increased PI3K→PDK1→AKT Thr308 phosphorylation. Simultaneously, mTORC2 (not inhibited by rapalogs) continues to phosphorylate AKT Ser473 for full activation. The net result is elevated AKT activity during mTORC1 inhibition — the opposite of the intended effect — which limits the apoptotic response and is a key reason mTORC1 inhibitors have modest single-agent efficacy. Catalytic mTOR inhibitors (INK128, gedatolisib) inhibit both complexes and avoid this paradox.

Question 5

What is the difference between rapalogs and catalytic mTOR inhibitors?

Accepted Answer

Rapalogs (everolimus, temsirolimus) are allosteric inhibitors that bind FKBP12 and the FKBP12-rapamycin binding domain of mTOR, sterically preventing RAPTOR from positioning substrates for mTORC1 phosphorylation — they inhibit mTORC1 but not mTORC2. Catalytic (ATP-competitive) mTOR inhibitors (INK128/sapanisertib, gedatolisib) bind the mTOR kinase catalytic site in both mTORC1 and mTORC2, blocking all mTOR kinase activity simultaneously. Catalytic inhibitors therefore also suppress mTORC2→AKT Ser473 phosphorylation, avoiding the paradoxical AKT activation that limits rapalogs. However, they have broader toxicity profiles and the superior therapeutic index expected from complete mTOR blockade has not always translated clinically.

Question 6

Which cancers have activating mTOR kinase mutations and can they be targeted?

Accepted Answer

Activating mTOR kinase domain mutations occur in ~5% of clear cell renal cell carcinoma (most prominently E2014K, E2419K, L2427Q in the kinase domain FATC region), ~7% of bladder cancer, and occasionally in endometrial and breast cancer. These mutations create constitutive mTOR kinase activity independent of upstream RHEB-GTP input. Retrospective analyses suggest that renal cell carcinoma patients with activating mTOR mutations derive superior benefit from everolimus compared to wild-type mTOR tumours — consistent with oncogene addiction to mTOR kinase activity. This represents an emerging molecular biomarker for mTOR inhibitor selection, though prospective validation in dedicated biomarker-selected trials is ongoing.

MTOR Gene Function

Overview

More Apoptosis Regulators