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Path - Application of Molecular Pathology (ii) (EGFR (most commonly +ve in…
Path - Application of Molecular Pathology (ii)
Cetuximab
anti-EGFR monoclonal Ig
and now also panitumumab
originally companion Dx wasn't accurate
same response in EGFR +ve + -ve cases
why? they were using the wrong biomarker!
correct one = kras or nras
constitutively active when mutated
must be mutated for Tx to work
Trametinib
MEK inhibitor (downstream)
MEK normally activated by Raf
good response when BRAF mutated
BRAF + MEK inhibition > 1 alone
EGFR
most commonly +ve in adenocarcinoma
also tested for in non-small cell lung cancer + sometimes squamous (only a small % +ve)
most commonly in Asians + non-smokers
will respond to Erlotinib
tyrosine kinase R
Other targeted Tx in lung cancer
immunotx
checkpoint inhibitors
in programmed death ligand 1 (PDL1) +ve patients
PDL1 on tumour cell's binds to host T cells to prevent tumour killing
other uses: melanoma, CR cancer, urologic malignancies
Methods of developing tumour resistance to targeted Tx
activation of alternative pathways
aberrant behaviour of downstream activators (without R activation)
new mutations
e.g. T790M point mutation
resistant to tyrosine kinase inhibitors except 3rd gen
Future Developments
BRCA testing in ovarian carcinoma
PARP inhibitors
inhibit enzyme poly-ADP ribose polymerase
helps repair damage
lead to synthetic lethality (combination of deficiencies lead to cell death)
liquid BX
tumours shed DNA into blood (mutations detectable here)
non-neoplastic uses
Bx an organ to predicts rejection before transplant
distinguish IBDs (Crohn's vs Ulcerative Colitis)