Lung Carcinoma

Question 1

Growth factor receptor-related drivers in lung carcinoma

Answer 1

EGFR (ERBB1)
HER2 (ERBB2)
KRAS
BRAF
ALK
MEK1
MET1
NRAS
PIK3CA
ROS1
RET
NTRK

Question 2

Frequency of lung adenocarcinoma drivers

Answer 2

Question 3

Frequency of acquired resistance mechanisms in lung adenocarcinoma patients treated with 1st generation TKIs

Answer 3

Question 4

EGFR T790M

Answer 4

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.

Question 5

EGFR mutations are present in __% of lung adenocarcinomas

Answer 5

20-30%

Question 6

Most common activating EGFR point mutation

Answer 6

L858R

Located in exon 21

Question 7

Second most common group fo activating EGFR mutations

Answer 7

In-frame deletions nested around residues 747-750

Located in exon 19

Question 8

Together, L858R and residue 747-750 in-frame deletions constitute __% of pathogenic EGFR mutations found in lung adenocarcinoma.

Answer 8

80-90%

Question 9

Rare EGFR mutations associated with primary TKI resistance

Answer 9

Exon 20 insertions

Point mutations including:
S768I
L474S
D761Y
T854A

Question 10

Third most common group fo activating EGFR mutations

Answer 10

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

Question 11

ALK fusions in lung adenocarcinoma

Answer 11

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.

Question 12

Drugging ALK-rearranged lung adenocarcinomas

Answer 12

The ALK inhibitor Crizotinib is used

EGFR TKIs do not typically work well in these patients.

Question 13

Rate of BRAF mutations in lung cancer

Answer 13

2-3% of lung adenocarcinomas have a BRAF mutation, 50% of which are BRAFV600E

Question 14

Do approved BRAF inhibitors work on non-V600E BRAF mutations?

Answer 14

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.

Question 15

Common fusion partners with RTKs in lung adenocarcinoma

Answer 15

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.

Question 16

ROS1

Answer 16

Orphan receptor tyrosine kinase with no known ligand.

Bears homology to ALK.

Fusions involving ROS1 are found in 2% of lung adenocarcinomas.

Question 17

Drugging NTRK

Answer 17

NTRK fusion tumors are susceptible to larotrectinib

Question 18

KRAS in lung adenocarcinoma

Answer 18

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.

Question 19

KRAS mutations in never smokers/non smokers

Answer 19

Tend to be transition mutations (substitution of purine to purine or pyrimidine to pyrimidine)

G12D, G12S

Question 20

KRAS mutations in current or former smokers

Answer 20

Tend to be transverison mutations (substitution from purine to pyrimidine or vice versa)

G12C, G12V, G13C

Question 21

HER2 in lung adenocarcinoma

Answer 21

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.

Question 22

MET in lung adenocarcinoma

Answer 22

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.

Question 23

RET in lung adenocarcinoma

Answer 23

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.

Question 24

PIK3CA mutations in lung adenocarcinoma

Answer 24

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.

Question 25

MAP2K1 / MET mutations in lung adenocarcinoma

Answer 25

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.

Question 26

FGFR3 in lung adenocarcinoma

Answer 26

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.

Question 27

Possible acquired resistance mechanisms to first and second generation EGFR TKIs

Answer 27

• MET amplification
• ERBB2 amplification
• Small cell transformation

Question 28

Sensitivity to crizotinib therapy

Answer 28

Crizotinib has two possible targets:
ROS1 translocations
ALK translocations