PCL486H1 Lecture Notes - Lecture 7: Irs1, P70-S6 Kinase 1, Sirolimus
26 Feb 2017
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S6K-IRS1 feedback
• When activated by mTORC1→ S6K1 directly phosphorylates the insulin receptor substrate-1 (IRS1)
o Promotes IRS1 degradation stops signal downstream of receptor tyrosine kinase (RTK).
• Feeds back and phosphorylates IRS, another feedback telling the cell to stop growth from PI3K.
• Blocking mTOR with rapalogs was found to activates PI3K signaling and AKT
o Decrease S6K-1→ no inhibitory phosphorylate on of IRS-1→ PI3K binding→
PIP3→PH→PDK1
• PI3K activity is activated→ activates AKT→ activates mTOR even more.
o AKT has has hundreds of substrates→ disaster→ stops therapies.
• In tumor, high levels of p-AKT→ addition of Rapamycin which blocks cell growth→
o An increase of ATK occurs.
o There is also a second feedback in the ERK pathway.
• FKBP also doesn’t bind to mTORC2… therefore not effective for mTORC2
Rapalogs are not effective against mTORC2
• mTOR inhibitors in clinical development
• Rationale for kinase inhibition:
o Inhibition of both mTORC1/2 would have a greater impact on cancer cells,
o Several groups have developed small molecules that directly inhibit mTOR kinase.
o So why don’t we block the kinase function, and then block mTOR1/2.
• Kinase inhibitors: kinase inhibitors of mTOR which are ATP competitors
o kinase inhibitors block that catalytic function of mTOR in both mTORC1/2:
▪ Directly blocks kinase domain→ blocks both mTORC1/2
Kinase inhibitors block both mTORC1/2 - AZD
• Because mTORC2→ Causes activation of AKT VIA Ser473 phosphorylation
o KI inhibitors block the feed back that happens during Rapamycin treatment (alone).
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Pip3 ph pdk1: pi3k activity is activated activates akt activates mtor even more, akt has has hundreds of substrates disaster stops therapies. Rapalogs are not effective against mtorc2: mtor inhibitors in clinical development, rationale for kinase inhibition: Dual mtor-pi3k inhibition: limitations: lack of biomarkers, better understanding of mechanism still required, stratification of patients and selection of drug combination therapies, more effective and personalized cancer therapy. Mapk pathways: start: binding of ligand to transmembrane protein; an rtk, there are 4 families, erk (classicals) most mutated oncogenes, c-jun- n-terminal kinase (jnk/sapk) p38 kinase pathway, erk5. In the off state (gdp), it is bound to the nucleotide guanosine diphosphate: activation and deactivation is controlled by cycling between gtp and gdp. Ras activation: gefs and gaps: exchanging nucleotide exchange factors (gefs): sos- gefs facilities the activation of ras, gtpase activating proteins (gaps): ras-gap: accelerate ras inactivation.
