Lung Carcinoma Flashcards
Growth factor receptor-related drivers in lung carcinoma
EGFR (ERBB1)
HER2 (ERBB2)
KRAS
BRAF
ALK
MEK1
MET1
NRAS
PIK3CA
ROS1
RET
NTRK
Frequency of lung adenocarcinoma drivers
Frequency of acquired resistance mechanisms in lung adenocarcinoma patients treated with 1st generation TKIs
EGFR T790M
Most common resistance mutation to 1st generation TKIs
Very commonly acquired after 10 months of TKI therapy, approximately 50% of cases
Reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs. Also appears to have its own contribution to cell survival.
The T790 in EGFR is located at a key position in the ATP binding cleft, often referred to as the “gatekeeper residue.” It was previously thought that mutation of this site produced resistance through steric hinderance, but now the ATP affinity explanation is preferred due to the results of mechanistic studies.
Interstingly, the T790 locus of EGFR is analogous to the T315 locus of ABL, which can also acquire imatinib resistance via the T315I mutation.
EGFR mutations are present in __% of lung adenocarcinomas
20-30%
Most common activating EGFR point mutation
L858R
Located in exon 21
Second most common group fo activating EGFR mutations
In-frame deletions nested around residues 747-750
Located in exon 19
Together, L858R and residue 747-750 in-frame deletions constitute __% of pathogenic EGFR mutations found in lung adenocarcinoma.
80-90%
Rare EGFR mutations associated with primary TKI resistance
Exon 20 insertions
Point mutations including:
S768I
L474S
D761Y
T854A
Third most common group fo activating EGFR mutations
Insertions in exon 20
Account for approximately 10% of all mutations
Highly variable in position and size, but generally occur within a hotspot region between codons 767 and 774
ALK fusions in lung adenocarcinoma
Identified in 3-7% of lung adenocarcinomas
Most frequently ALK::EML4, but ALK::KIF5B and ALK::TGF are also seen.
Most commonly found in never smokers or light smokers of a younger age.
Morphologically associated with a signet ring adenocaricnoma morphology, but not always.
Drugging ALK-rearranged lung adenocarcinomas
The ALK inhibitor Crizotinib is used
EGFR TKIs do not typically work well in these patients.
Rate of BRAF mutations in lung cancer
2-3% of lung adenocarcinomas have a BRAF mutation, 50% of which are BRAFV600E
Do approved BRAF inhibitors work on non-V600E BRAF mutations?
At this time, there is not good evidence for effectiveness in non-BRAFV600E BRAF mutations and fusions.
From what we do have, both mutation-specific BRAFV600E inhibitors and MEK inhibitors do not seem to be very effective in these alternative BRAF variants.
Common fusion partners with RTKs in lung adenocarcinoma
CD74 and TPM3 are seen in multiple fusions.
CD74 is the class II MHC gamma chain.
TPM3 is a tropomyosin found in non-muscle cells.
ROS1
Orphan receptor tyrosine kinase with no known ligand.
Bears homology to ALK.
Fusions involving ROS1 are found in 2% of lung adenocarcinomas.
Drugging NTRK
NTRK fusion tumors are susceptible to larotrectinib
KRAS in lung adenocarcinoma
The name comes from the Kirsten rat sarcoma viral oncogene homolog, V-Ki-ras2.
KRAS mutations are found in 30% of lung adenocarcinomas. The vast majority of mutations are in codons 12 or 13, and less frequently in codon 61.
KRAS mutations in never smokers/non smokers
Tend to be transition mutations (substitution of purine to purine or pyrimidine to pyrimidine)
G12D, G12S
KRAS mutations in current or former smokers
Tend to be transverison mutations (substitution from purine to pyrimidine or vice versa)
G12C, G12V, G13C
HER2 in lung adenocarcinoma
In lung adenocarcinoma, we most commonly see activating mutations in the TKD of HER2. This is seen in 2-4% of lung adenocarcinomas overall.
In-frame insertions in exon 20 are most common, but TKD point mutations are also seen.
Insertions of 3-12bp in length are confined to a hotspot region between codons 775 and 881.
The most common is A775_G776insYVMA, representing 80% of HER2 driver mutations in lung adenocarcinoma.
HER2 driven lung adenocarcinomas can be targeted with trastuzumab.
MET in lung adenocarcinoma
Aka the hepatocyte growth factor receptor, another RTK with roles in embryonic development and wound healing
Deregulation through mutation or amplification is associated with the activation of RAS, PI3K, STAT3, and beta-catenin pathways.
Activating somatic mutations that affect the splice site regions of exon 14 are seen in 4% of lung adenocarcinomas. Loss of these splice sites leads to exon 14 skipping and resultant deletion of the juxtamembrane domain of the MET receptor, resulting in enhanced signaling.
Amplification is also seen in 2-4% of lung adenocarcinomas, and is associated with primary resistance to EGFR inhibitors.
Mutations confer sensitivity to targeted MET inhibitors.
RET in lung adenocarcinoma
RET (rearranged during transfection) is another RTK, which plays a critical role in neural crest development. It is normally dependent on the glial cell-line derived neurotropic factor (GDNF) family of ligands as well as the co-receptor GRFa1. The wild-type receptor is activated by dimerization when ligand is present.
In 1% of lung adenocarcinomas, a RET fusion is present. Several partner genes have been described (CCDC6, KIF5B, NCOA4, TRIM33, CUX1, KIAA1468).
Few RET-specific inhibitors are available, such as Selpercatinib (approved June 2024). There are also several broader spectrum RTK inhibitors with RET coverage.
PIK3CA mutations in lung adenocarcinoma
Encodes the p110a subunit of PI3K, a downstream signaling component in mitogen pathways. PIK3CA activates AKT, which in turn activates mTOR.
PIK3CA mutations are found in 2% of lung adenocarcinomas.
Mutations occur in two hotspot regions in exons 9 and 20, encoding the helical and kinase domains repsectively.
E545K and H1047R variants comprise approximately 80% of pathogenic mutations identified in lung adenocarcinoma.
Five FDA approved PIK3CA inhibitors are on the market, including umbralisib, copanlisib, duvelisib, alpelisib, and idelalsib.
MAP2K1 / MET mutations in lung adenocarcinoma
Dual specificity kinase with the pivotal role in the signal intergration of the MAPK/ERK cascade.
Mutations are found in 1% of lung adenocarcinoma with a higher prevalence among smokers, and involve constitutively activating point mutations.
K57N and G56P are the most common.
The slective MAP2K1 inhibitor trametinib is currently available and FDA approved in combination with dabrafenib for patients with metastatic lung adenocarcinoma harboring the BRAFV600E mutation.
FGFR3 in lung adenocarcinoma
Fibroblast growth factor receptor 3
Found in 1-2% of NSCLCs, but more frequently SCC than adenocarcinoma.
Commonly reported mutations include R248C, S249C, G370C, and K650E.
The fusion FGFR3::TACC3 is also reported in lung SCC, lung adenocarcinoma, and in papillary urothelial carcinoma.
Possible acquired resistance mechanisms to first and second generation EGFR TKIs
- MET amplification
- ERBB2 amplification
- Small cell transformation
Sensitivity to crizotinib therapy
Crizotinib has two possible targets:
ROS1 translocations
ALK translocations
