Novel inhibitors of cell proliferation

Question 1

PI3K pathway in cancer

Answer 1

Activated by KRas

converts PIP2 to PIP3 which then activates AKT.

AKT signals through mTOR to increase cell survival and cell cycle progression.

Mutations to the catalytic subunit of PI3K lead to enhanced mTOR activation. this can lead to the development and resistance of cancer - includes HER2+ breast cancer. increases likliness of tumour metastasis. 70% of brain metastasis patients see enhanced PI3K pathway.

Question 2

Drugs targeting the PI3K pathway

Answer 2

Idelalisib, copanlisib, and alpelisib are PI3K inhibitors. Pictilisib is one that is in phase 2 clinical trials.

Capivasertib is an Akt inhibitor approved for breast cancer treatment

Everolimus and temsirolimus are mTORC1 inhibitors for advanced renal cancer and pancreatic tumours

paxalisib is a dual PI3K and mTOR inhibitor that penetrates the BBB. currently in phase 2 clinical trials. also found to reduce brain metastasis when used with trastuzumab in preclinical studies.

Question 3

KRas role in cancer

Answer 3

KRas overactivaiton found in 90% of pancreatic ductal adenocarcinomas

43% of colorectal

25-30% of lung adenocarcinoma and 30-35% of NSCLC.

KRasG12C is a mutation of KRas that is found in 25-35% of smokers (compared to 5% in normal pop). it increases KRAS activity

KRas activates the PI3K/Akt/mTOR and the Raf, MEK, ERK pathways to mediate cell proliferation and survival

KRAS increases the expression of PD-L1 which decreases MHC expression. they reduce immune function leading to “immune escape” of cancer cells.

Question 4

Targeting KRAS in cancer

Answer 4

sotorasib targets the KRASG12C mutation. used in NSCLC. covalent

adagrasib is a orally active small molecule covalent inhibitor selective to KRASG12C, approved for KRASG12C+ NSCLC

They lock the protein in an inactive GDP-bound state

Question 5

Cyclin-dependent kinases in cancer and drugs targeting them

Answer 5

they are activated by the PI3K/Akt/mTOR and ERK pathways. D-type cyclins are increased by the Ras/Raf/MAPK pathway. GSKbeta is responsible for exporting Cyclin D1 out of the nucleus. PI3K pathway inhibits GSKB.

As such, over activation of RAS leads to increased expression of cyclin-D1 and it is kept in the nucleus.

They control cell cycle and thus proliferation.

CDK 4 and 6 promote the entry of cells into the cell cycle.

CDK4/6-cyclin-D and CDK2-cyclin-E complexes phosphorylate retinoblastoma (RB) proteins. RB has growth suppressing effects. this phosphorylation inactive RBs, leading the cell to progress from G1(growth phase 1) into the S phase (dNA synthesis).

Ribociclib and Palbociclib are CDK 4 and 6 inhibitors. they treat hormone receptor + and HER2- tumours that have metastasised.