Sweatman: Lung Cancer Drugs Flashcards
(101 cards)
basis for treament of lung cancer: NSLC
- often able to resect surgically
- more targetted therapies
- histological subtype should always be reported
basis for tx. of SCLC
- usually mets at time of dx. therfore not surgically resectable most often
- demonstrate a high sucseptibility to tx. but usually a relaps in 8 mos with a more lethal form of cancer causing deaht in 4mos on average
dx of NSCLC requires
explicit reporting if histo-subtype
EGFR mutations found in/not found in
found in adenocarcinomas
not found in Large cell, small cell, pure squamous carcinomas
Bevacizumab is associate with what side effect
ONLY PPROVED IN NON-SQUAMOUS NSCLC’S
high risk of bleeding in squamous lung cancers and therefore only
what are dirver mutaitons and passenger mutations
driver-> critical for cell-growth or survival
passenger-> mutations that accumulate not directly linked to survival or growth advantage
why are driver mutations important targets
drugs targetting newly critical driver enzymes can be highly effective agents because cancer cells are often times become reliant on these pathways at the expense of other previously critical cell-survival pathways (OVERDEPENDENCE MECHANISMS)
*TARGETTING PASSENGER MUTATIONS DOES NOTHING
DESCRIBE SYNTHETIC LETHALITY
IN A NORMAL CELL–> YOU MUST INACTIVATE 2 MUTATIONS A+B IN ORDER TO COMPROMISE CELL VIABILITY–> INACTIVATION OF A SINGLE GENE DOES NOT KILL CELL–> REMAMINING GENE ACTS IN A COMPENSATORY MANNER
*SYNTHETIC L;ETHALITY IN A CANCER CELL WITH A MUTATED GENE A NOW MAKES THE CELL VULERABLE BECAUSE B IS NOW A SOLE TARGET TO KILL THE CELL–> A CANNOT COMPENSATE
HOW does egfr receptor work
egf–egfr= dimerization and tyrosine residue trans-phophorylation–> signals to the nucleus–> cell growth and proliferation–> avoidance of apoptosis
GOF in this pathway=some cancers
GOF mutations in egfr result in
- receptor amplification
- mutation
- translocation
* self sufficiency in cell signalling–> anti-apoptotic
TKI’s work to
inhibit signal propagation from the dimerized TKR–> cell does not receive proliferation signal and undergoes apoptosis
mechanisms of reistance to TKI’s at the level of the EGFR
ALL OF WHICH LEAD TO SURVIVAL SIGNALS
- binding site mutation (small molecule no longer bind tkr)
- amplified met (AKA HGFR)–> compensatory trans-phosph
- HGF assuming independent role in the proliferativesignalling process
resistance to TKI’s regarding pro-apoptotic proteins
other than tki binding site mutations
- polymorphisms in apoptosis genes–> BIM
a. absence of pro-apoptotic gene BH3
bBAX and BAk downregulated while BCL2 and MCL1 are upregulated (anti-apoptotic)
TKI resistance downstream of EGFR
KRAS mutations
*negative response predictor in lung/colorectal cancer
BRAF mutations
mechanism of resistance that renders a tumor line unresponsive to TKI’s
KRAS and BRAF
*downstream of TKR/EGFR complex
targeted therapy most usful in compatting which lung cacinoma sub-type
adenocarcinoma
ALK stands for
anaplastic lymphoma kinase
EML4/ALK arises from what and does what?
fusion of these two genes translocation–> activates ras raf MEK/ERK pathway and promotes cell proliferation
anti-AML4/ALK drug
crozitinib
anti-vegf drug
bevacizumab
proliferation/ mets of solid tumurs requires…
formation of new vasculature
how does a tumur go about neo-vascularization
sensing HIF1–> releasing VEGF in hypoxic states (HIF1 is not destroyed by VWF in truly hypoxic states(–. goes to nucleus and causes transcription of VEGF->neovascularization
down sides to bevacizumab therapy
- reduce distribution of concurrent chemotherapy
- induce accumulation of more aggressive cells (with increased capacity to spread to other organs)
* applies a major selective pressure on 2-independent cell population–> can make them more resistant to tx.
distribution of orally administered crozitinib (aml), erlotinib (egfr) and lapitinib (vegfr tki) is effected by
Must be absorbed in the gut and small intestines
metabolism depends on bioavailability and host pharmacogenetics
