Cancer Flashcards
PI3K/Akt/mTOR Pathway
PI3K catalyses the conversion of PIP2 into PIP3.
PIP3 recruits Akt to the membrane, and PDK1 and mTORC2 then activate it.
Activated Akt promotes cell growth and survival via mTORC1.
In cancer, mutations in the catalytic subunit cause PI3K to be hyperactive, enhancing the activation of mTORC1.
This can cause can cause as well as resistance to cancer treatment, such as the resistance to Herceptin for HER2-positive breast cancer.
The tumour is more likely to metastasise. Enhanced activation of the PI3K pathway is seen in 70% of patients with brain metastases as a result of breast cancer.
PI3K/Akt/mTOR Pathway inhibitors
PI3K inhibitors include:
- Idelalisib – approved for blood cancers including chronic lymphocytic leukaemia (CLL). It selectively inhibits the delta isoform of PI3K.
- Copanlisib – approved for the treatment of relapsed or refractory follicular lymphoma.
- Alpelisib – approved for use in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer with PIK3CA mutations.
- Pictilisib – inhibitor in phase II clinical trial
mTORC1 inhibitors include:
- Everolimus – approved for the treatment of advanced RCC and pancreatic neuroendocrine tumors.
Temsirolimus – approved for the treatment of advanced RCC.
Dual PI3K/mTOR inhibitors include the investigational drugs:
- Bupalisib – in clinical trials for various cancer types including breast and endometrial cancers.
- Dactolisib – has shown activity in preclinical studies and early-phase clinical trials for several cancers.
- Paxalisib - brain penetrant - combination theraphy with Trastuzumab (Herceptin) reduces brain metastases in preclinical studies and is currently in pase II clinical trials.
Capivasertib is an Akt inhibitor approved last year as a breast cancer treatment.
KRAS Pathway
KRAS mutations are the most common oncogenic drivers in human cancers.
The KRAS pathway is implicated in:
- ∼ 90% of pancreatic ductal adenocarcinomas (PDAC)
- 43% of colorectal cancers (CRC)
- 25–30% of lung adenocarcinoma
- 30–35% of non-small cell lung cancers (NSCLC)
The KRAS protein activates multiple signalling pathways, including ERK signalling and the PI3K/Akt/mTOR signalling pathway.
These pathways mediate cell proliferation and survival downstream of growth factor receptors and tyrosine kinase receptors.
The KRAS G12C mutation, a substitution of glycine by cysteine, results in constitutive activity, which drives cancer.
The incidence of KRAS mutations is 25-35% in smokers and 5% in non-smokers.
KRAS mutants were previously considered ‘undruggable’ as there is no binding pocket on this protein, but it can now be targeted by small molecular inhibitors which covalently bind to the cysteine residue.
KRAS mutations are implicated in shaping the tumour microenvironment (TME), creating an inflammatory environment by increasing the secretion of cytokines and chemokines like IL-6 and IL-8.
KRAS can also drive “immune escape” in cancer cells by:
- Increasing the expression of PD-L1. PD-L1 binds to PD-1, a protein on T cells. This prevents T cells from killing the cells that have PD-L1, helping cancer cells hide from the immune system.
- Decreasing MHC expression
- Producing immunosuppressive factors like IL-10 to reduce immune cells function
- Suppressing the expression of T cells and myeloid-derived suppressor cells (MDSCs).
Cancer cells can therefore escape the immune system.
KRAS inhibitors
KRAS G12C inhibitors covalently bind to the cysteine residue at position 12 of mutant KRAS to block KRAS activity and downstream signalling.
Inhibitors can be used to treat cancers where this mutation is present.
Sotorasib was licensed in May 2021 for the treatment of NSCLC.
Adagrasib is a potent, orally available inhibitor, approved in December 2022 by the FDA for NSCLC.
These covalent inhibitors irreversibly lock KRAS G12C in the inactive GDP-bound state.
Proteolysis-targeting chimeras (PROTACs) could also be used against the mutant KRAS.
PROTACs are bivalent molecules that link a small molecular inhibitor to a degrader that binds a ubiquitin E3 ligase, hijacking the ubiquitin-proteosome system.
The aim is to enhance ubiquitination and proteasomal degradation of the protein, as well as pharmacological inhibition.
Adagrasib was also found to act as PROTAC, marking the KRAS protein for degradation.
Despite the encouraging initial results with KRAS G12C inhibitors, resistance mechanisms have emerged. These mechanisms can include secondary KRAS mutations (e.g., Y96D) that affect drug binding, as well as the activation of bypass signalling pathways involving other RAS isoforms and RTKs.
Cyclin-dependent kinases (CDKs)
The PI3K/Akt/mTOR and ERK pathways downstream of KRAS lead to the activation of cyclin-dependent kinases (CDKs). These control the cell cycle and hence cell proliferation, so dysregulation causes uncontrolled growth and division.
CDK 4 and 6 are involved in promoting entry of the cell into the cell cycle.
The RB protein, part of the retinoblastoma family of proteins, actively suppressed cell division in the absence of appropriate signalling—it is a tumour suppressor.
RB is sequentially phosphorylated by CDK4/6–cyclin-D and CDK2–cyclin-E complexes.
RB holds the E2F transcription factor in place. Its phosphorylation allows the release of the transcription factor and initiation of DNA transcription, allowing cells to progress through G1 into the S phase.
There is a loss of control of the G1 phase in cancer. This can be due to CDK 4/6 or cyclin overexpression or a loss of RB activity.
The expression of D-type cyclins is increased by the Ras/Raf/MAPK pathway as this pathway targets the c-Myc transcription factor, which regulates expression of cyclin D.
Cyclin D1 is a key regulator of cell cycle progression. It is exported from the nucleus by glycogen synthase kinase 3-β (GSKβ) to prevent excess cyclin D1.
GSKβ is inhibited by the PI3K/AKT pathway, so this pathway prevents cyclin D1 export out of the nucleus.
Therefore, the Ras/Raf/MAPK pathway increases expression of cyclin D1 and the PI3K/AKT pathway keeps it in the nucleus. This results in excess cyclin D1 in the nucleus and therefore excess cell proliferation.
Overactivity of these pathways, or of KRAS upstream of both, can result in increased cell proliferation and therefore cancer.
