Flashcards in Lung Cancer Drugs Deck (63)
What drug is only approved for treatment of non-squamous NSCLCs? Why?
Bevacizumb because it is associated with a high risk of bleeding
Drugs that end in 'nib' are what?
tyrosine kinase inhibitors
How do EGF receptors work?
In the normal cell, binding of a ligand to the receptor results in dimerization and tyrosine residue trans-phosphorylation. This initial event is transduced to the nucleus where effects upon nuclear transcription can
lead to cell growth, proliferation and the avoidance of apoptotic events.
What the EGFR IgG monoclonals approved for treatment of SQUAMOUS NSCLC?
How do EGFR monoclonals work?
competitively block binding of EGF and TGF-a to EGFR, thereby inhibiting receptor autophosphorylation
What step in the signaling pathway do TKIs inhibit? Result?
the phosphorylation step is
inhibited and the absence of proliferative signal leads to an apoptotic response.
How can resistance to TKIs arise?
-Drug binding site mutation (T790M!!!),
-Compensatory phosphorylation of the tyrosine residues (ERBB3) via MET, also known as hepatocyte growth factor receptor (HGFR) which itself possesses tyrosine kinase activity, or
-By HGF assuming an independent role in the proliferative signaling process independent of ERBB3 or EGFR
Where do TKIs bind?
the tyrosine kinase domain of EGFR at the ATP binding site
What are some common drug site mutations to TKIs that make them MORE effective?
-in-frame deletions at exon 19 or point mutations in exon 21 (L858R) in NSCLC
What are some common drug site mutations to TKIs that make them LESS effective?
A T790M (exon 20) mutation reduces the drug activity by preventing correct orientation of drug binding on the active site.
The T790M mutation (part of ATP binding site) may
simply be an outgrowth of pre-existing clones that are inherently resistant, because such mutations can be determined in patients who have never received one of the
What happens when the EGFR is phosphorylated?
KRAS, BRAF, MEK, to ERK/MAPK that promotes proliferation, angiogenesis, survival etc in the nucleus via transcription
Describe the EML4-ALK oncogene mutation.
Translocations pair these two to produce constitutive tyrosine kinase activity independent of EGF which produce activation of the MEK/ERK, P13K, and JAK-STAT pathways and cell proliferation
What patient population commonly has a EML4-ALK mutation?
nonsmokers, light smokers, and in adenocarcinomas
When is VEGF released normally?
lack of O2 stimulates HIF-1 to release VEGF to stimulate angiogenesis
What is a large supply of VEGF important for?
solid tumor growth
What are some of the downsides of using VEGF inhibitors?
-reducing the distribution of concurrent chemotherapy without a blood supply
-induces accumulation /selection of more aggressive cells
What mutations are more common in smokers?
-G:C to T:A mutations
-p16 and APC methylation
What mutations are more common in NON-smokers?
What are the most common mutations in lung adenocarcinoma?
recommend routine testing for EGFR and ALK rearrangements in all adenocarcinomas
What is the most commonly used method in most EGFR studies?
What is the preferred method of testing for ALK rearrangements?
T or F. The USPSTF recommends that all heavy smokers with a 30+ pack-year history undergo routine low-dose CT scans for small (and thus very treatable) tumors
What is the best treatment for solid tumor?
surgical resection with drugs neo- or adjuvantly
Does metastasis occur earlier in SCLC or NSCLC cancers?
SCLC (so chemo/radiation is usually the only option)
What is the standard treatment of SCLC?
Etoposide + cisplatin+ carboplatin
What is the standard treatment of NSCLC?
Cisplatin AND paclitaxel, docetaxel, irinotecan, gemcitabine, vinorelbine, or pemetrexed
What is the preferred maintenance drug for NSCLC?
Pemetrexed, a DHFR inhibitor
When is pemetrexed maintenance indicated?
For patients with stable or responding disease following 4 cycles of nonpemetrexed-platinum combo chemo
When is Bevacizumab indicated?
for patients with non-squamous histology, no brain metastases, and no hemoptysis