Non small cell lung cancer Flashcards
describe some characteristics of NSCLC
- Non-Small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers (Small cell lung cancer (SCLC) accounts for 15-20% of all lung cancers)
- Seen in smokers and non-smokers.
- Less aggressive than SCLC
- 5-year survival rate of 23%.
- More responsive to targeted therapies (relatively insensitive to chemo) than SCLC.
where does NSCLC typically arise from?
Arises from the epithelial cells of the lung or of the central bronchi to terminal alveoli
The histological type correlates with the site of origin. Therefore, where does adenocarcinoma and squamous cell carcinoma originate from?
Adenocarcinoma usually originates in peripheral lung tissue.
Squamous cell carcinoma (which is also called epidermoid carcinoma) forms in the lining of the bronchial tubes.
which is the most common form of lung cancer?
Adenocarcinoma is the most common form of lung cancer among both men and women.
what do large cell carcinomas refer to?
Large cell carcinomas refer to non-small cell lung cancers that are neither adenocarcinomas nor epidermoid cancers.
describe the staging of NSCLC using the TNM system
unlike small cell lung cancer, which is staged into limited or extensive: NSCLC is staged into stage 1, stage 2 and stage 3
what does TNM stands for?
T: size of the primary tumour
N: Status of the lymph node
M: metastasis presence
describe some of the mechanisms of NSCLC development
- Treatment decision for NSCLC patients has been historically based on the tumour histology classification
- However, with the novel sequencing technologies= we can extract the molecular profile of the tumours and create a gene list that are present in the effective patients
- NSCLC present KRAS mutations in many cases, followed by alterations in the EGFR gene–>BRAF gene–. other genes
- Almost all these genes are targetable
- Only problem: no targetable treatment for KRAS mutations but there lots of clinical trials testing inhibitors of MEK and other pathways where KRAS is involved
- EGFR: Erlotinib, gefitinib, afatinib, osimertinib
- BRAF: Dabrafenib, trametinib, vemurafenib
Going to focus on ALK oncoprotein fusion, BRAF and EGFR mechanisms of NSCLC and its treatment
what are the treatment strategies for NSCLC?
• Chemotherapy (when no known driver mutation) • Radiotherapy (in patients with no receptable disease--> local control can be achieved) • Surgery • Targeted treatments: EGFR antagonists BRAF inhibitors ALK inhibitors Anti-angiogenics (in combination)
describe the association of EGFR and NSCLC
- 10-20% NSCLC
- Mutations in EGFR gene cause protein/receptor overexpression
- Most common forms: del19 or exon 21 mutation (L858R)
- Associated with a worse prognosis
- HER1/EGFR gene encodes for part of the human epidermal growth factor receptor
- Receptor function requires receptor dimerization and growth factors binding
what can be used to predict non-responsiveness to molecular targeted therapies such as EGFR inhibitors?
KRAS is used and serves as a predictor of non-responsive to molecular targeted therapies such as EGFR inhibitor–> therefore when they’re mutated at the same time= useless to target EGFR as patient won’t respond to targeted therapy
describe EGF-EGFR signaling
- All the downstream pathways that are controlled by the activation of the EGF receptor
- EGFR acts as a tyrosine kinase: in the intracellular domain there is tyrosine kinase activity
- Tyrosine kinase activity includes phosphorylating its effectors’ tyrosine residues. For this phosphorylation it requires an ATP molecule (ATP–>ADP…uses phosphate group to phosphorylate tyrosine amino acid of its effectors)
- Tyrosine kinase activity of EGFR is within the intracellular domain–> the phosphorylation of downstream effectors causes the activation of so many pathways/signalling cascades that are going to control the cell proliferation, apoptosis, invasion and angiogenesis etc.
Name and describe some EGFR tyrosine kinase inhibitors (TKIs)
Iressa- commercial name (gefitenib) and Tarceva-commercial name (erlotinib)
- Initial results of phase 2 trials testing erlotinib and gefitinib in unselected patients were modestly positive but disappointing.
- BR.21 Phase III:erlotinib–> Median survival 6.7 vs 4.7 months, 8.8% response rate. Led to FDA approval of erlotinib as second/third line treatment after chemotherapy in NSCLC.
In BR.21 study, 10% of patients treated with either erlotinib or gefitinib were dramatic responders (responded really well) • Females+ • Adenocarcinoma + • Asian ethnicity + • Non-smokers
= they found they had a different type of mutation–> affecting the EGFR gene
There are mutations associated with drug sensitivity and others with drugs resistance i.e. patients that have the EGFR gene, don’t respond to erlotinib as they present some mutations that confer some resistance to the drug… one of the mutations is the T7090M
what is the difference between phase 2 and phase 3 clinical trials?
Phase II: try to find the main side effects of the treatment from the studied drug and its efficiency (no comparison of new treatment with gold standard treatment. Sample size is also smaller.
Phase III: larger sample than phase II (100s-1000s of patients), compare the new treatment with the traditional treatment (erlotinib vs chemotherapy)
what is T790M?
T790M is the most common mechanisms of resistance to EGFR TKI (60-70%) THEREFORE there is a need to find another treatment (third generation tyrosine kinase inhibitor that binds to the receptor even when there is T790M)
Why are liquid biopsies important?
Liquid biopsies: the sampling and analysis of liquid tissue (e.g. blood)–>can isolate circulating tumour cells and circulating tumour DNA from blood–> can detect somatic mutations e.g. T790M mutation= helps for the treatment decision making process
why are liquid biopsies replacing solid tissue biopsies?
- less invasive
- allows scientists to analyse all the mutations present in the EGFR gene of patients just by extracting blood sample.
- FDA approved
why is T790M such a problem?
- Erlotinib binds to the ATP binding pocket side of the tyrosine kinase domain of the EGFR protein= this doesn’t allow EGFR protein to use the ATP to phosphorylate the substrate
- HOWEVER, when EGFR is affected by T790M= there is a conformational change of the ATP binding pocket side of the tyrosine kinase domain of the EGFR protein= allows the ATP to bind= makes the receptors active regardless of erlotinib presence
describe a 3rd generation EGFR inhibitor
osimertinib:
- Irreversibly binds to C797 in the ATP binding site (Regardless of T790M mutation)
- Well tolerated in clinical trials.
- Approved for first- and second-line use, including after resistance mediated by T790M mutations.
what else is effective for the treatment of NSCLC when the affected gene is EGFR?
- Anti-EGFR mAbs now include cetuximab, necitumumab, panitumamab and matuzumab
- Effective for the treatment of NSCLC when the affected gene is EGFR
- Competitive inhibition of ligands (EGF) binding to the extracellular domain
- Also form antibody-receptor complexes that are endocytosed and degraded
associate BRAF to NSCLC?
- BRAF gene encodes for a serine/threonine kinase that belongs to the RAS-RAF-MEK-ERK axis that regulates cellular growth.
- BRAF mutations in up to 2-3% of the NSCLC patients.
- BRAF V600E account for 50% of the cases and affects to the tyrosine kinase domain= making it active
- Sorafenib and vemurafenib are tyrosine kinase inhibitors that target oncogenic BRAF.
- Efficient in melanoma but partial response in NSCLC.
BRAF-V600 phosphorylates MEK, which phosphorylates ERK=increases cell proliferation and survival.
Oncogenic BRAF signalling arrested with BRAF inhibitors.
Selective binding of oncogenic BRAF kinase by vemurafenib, blocks the constitutively activated pathway and downstream activity= decreases cell proliferation and survival.
Researchers are trying to extrapolate the findings/results from the mechanisms of resistance of this targeted therapy to melanoma–> may also find out the mechanisms of resistance of NSCLC towards this targeted therapy.
describe the ALK fusion oncogene EML4-ALK
- Result of an inversion in chromosome 2p, which results in the fusion of the N-terminal portion of the echinoderm microtubule-associated protein-like 4 (EML4) with the kinase domain of ALK.
- = EML4 is now controlling the tyrosine kinase domain of the ALK gene
associate EML4-ALK to NSCLC
- Present in 4% of patients with NSCLC.
- Typically, younger non-smokers lacking mutations in either EGFR and KRAS.
- Crizotinib (targeted therapy) compete binding within the ATP-binding pocket of ALK.
describe normal conditions of ALK signalling compared to when crizotinib is used
Normal conditions: ALK (Receptor) phosphorylates some substrates–> when dimerization occurs= kinase domain will be permanently active and will permanently and abnormally activate the ALK signalling= permanent proliferation, cell growth, angiogenesis and inhibition of apoptosis
Crizotinib: binds to the ATP-bind pocket of ALK to inhibit the interaction of ATP use in downstream phosphorylation= switch off downstream pathways
How can VEGF be targeted?
- Can target angiogenesis
- Bevacizumab (Avastin®) is a monoclonal antibody that binds to VEGF and prevents its binding to VEGF receptors on endothelial cells= inhibit vascularisation + metastasis.
- Avastin approved for metastatic non squamous non-small cell lung cancer in combination with platinum chemotherapy.
there has been some progress in genomics; tissue is the issue. What are the challenged?
- Location of tumour: lung tumours are often difficult to access
- Biopsy: need sample of sufficient size and quality to isolate DNA
- Pre-analytical phase must be standardised
- Difficulty in obtaining adequate samples (i.e. size and quality of specimen)
Alternative? = LIQUID BIOPSIES TO STUDY THE MOLECULAR PROFILE OF NSCLC + FIND THE BEST THERAPIES THAT CAN TARGET THOSE GENES
Summary
- Non-Small Cell Lung Cancer (NSCLC) is any type of epithelial lung cancer other than small cell lung cancer (SCLC).
- NSCLC develops in smokers and non-smokers and shows better prognosis.
- The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma.
- The most frequently altered genes in NSCLC are KRAS, EGFR and BRAF.
- NSCLC are responsive to targeted therapies such as erlotinib (EGFR), sorafenib and vemurafenib (BRAF), crizotinib (ALK fusion oncogen) and bevacizumab (anti-angiogenic therapy).
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