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subsequently experience a recurrence. How this acquired BRAF mutation
resistance towards tyrosine kinase inhibitors occurs is not BRAF encodes a downstream signalling mediator of
fully understood, but secondary mutations in EGFR and KRAS. The BRAF protein activates the MAPK pathway.
amplification of the oncogene MET are common in these BRAF mutations have been observed in 1-3% of NSCLC
patients. The most common secondary EGFR mutation with adenocarcinoma variant and are usually associated
is the substitution of methionine for threonine at position with a history of smoking. For patients with a BRAF
[17]
790 (T790M). Another characteristic of the acquired V600E mutation, treatment with BRAF inhibitors such as
[12]
resistance is the amplification of the MET oncogene, which (dabrafenib andovemurafenib, or dabrafenib plus trametinib
is detected in 5-20% of patients with progressive disease to inhibit the MAPK pathway is recommended, rather than
while being treated with either erlotinib or gefitinib. In single-agent chemotherapy.
[13]
some cases, only MET amplification is present, while in
others, amplification and the secondary T790M mutation MET abnormalities
in EGFR are present. The absence of the MET oncogene Generally smoking-related and identified via IHC in 25-50%
amplification may be indicative of improved survival in of NSCLC specimens, MET expression also appears to be
[18]
patients with surgically resected NSCLC. [14] associated with a more severe prognosis. MET encodes
a RTK for hepatocyte growth factor (HGF). Abnormalities
ALK translocation include overexpression due to gene amplification and splice
Translocations involving ALK are present in approximately site alterations at exon 14 of the gene. In such patients,
4% of NSCLC adenocarcinomas in the United States, and treatment with a MET inhibitor (crizotinib or cabozantinib)
occur more frequently in non-smokers and younger patients. is recommended rather than single-agent chemotherapy as
In advanced NSCLC, the presence of an ALK translocation second-line treatment.
indicates sensitivity to ALK tyrosine kinase inhibitors such
as crizotinib and ceritinib, and treatment with these agents RET translocation
significantly prolongs progression-free survival. The RET gene encodes a cell surface RTK that is frequently
altered in medullary thyroid cancer. RET mutations
RAS mutations are encountered in younger patients and non-smokers.
Approximately 15-25% of patients with lung adenocarcinoma For patients with RET rearrangements, treatment with
have oncogenic KRAS mutations. The RAS family of a RET inhibitor such as cabozantinib or vandetanib is
proteins is a central mediator for the mitogen-activated recommended rather than single-agent chemotherapy as
[18]
protein kinase (MAPK), signal transducer and activator second-line treatment (Grade 2C).
of transcription (STAT), and phosphoinositide 3-kinase PIK3CA, AKT1, PTEN alterations
(PI3K) signalling pathways, which work together to control PIK3CA encodes the catalytic subunit of phosphatidyl
cell proliferation and apoptosis. The most common RAS 3-kinase (PI3K), which is an intracellular central mediator
mutation are missense substitutions in codons 12, 13, or 61. of cell survival signals. AKT1 acts immediately downstream
These mutations result in a constitutively active RAS due to of PI3K. PTEN dephosphorylates and subsequently inhibits
malfunctioning of the RAS GTPase. AKT. Oncogenic alterations in this pathway include gain-

ROS1 translocation of-function mutations in PIK3CA and AKT1, and loss of
PTEN function. Alterations in the PI3K signalling pathway
ROS1 translocation is associated with adenocarcinoma appear more frequently in patients who are smokers and
histology, and is typically observed in younger patients and with tumours of squamous histology. PIK3CA mutations
those who have never smoked. ROS1 is a RTK of the insulin also may promote resistance to EGFR inhibitors in EGFR-
receptor family. For these patients, first-line management mutant NSCLC. [19]
with crizotinib is recommended, instead of platinum-based
chemotherapy (Grade 1B). For patients who have received FGFR1 amplification
prior chemotherapy, treatment with crizotinib the preferred Fibroblast growth factor receptor-1 (FGFR1) is a cell
second-line chemotherapy (Grade 1A). [15] surface RTK that mediates cell survival and proliferation.
FGFR1 amplification has been detected in 13-25% of
HER2 mutation squamous tumours. FGFR1 amplification is associated
[20]
HER2 (ERBB2) encodes a RTK from the EGFR family. with smoking and with worse overall survival.
Mutations in HER2 have been detected in approximately
1-2% of NSCLC tumours, primarily adenocarcinomas. For CTNNB1 (β-catenin) mutation
patients with a HER2 exon 20 insertion mutation, a second- The CTNNB1 gene encodes β-catenin, a protein important
line targeted therapy with either afatinib monotherapy or for the regulation of epithelial cell growth. Mutations in this
trastuzumab in combination with singl- agent chemotherapy gene have been observed in approximately 2% of NSCLC,
(vinorelbine or docetaxel) is recommended, rather than particularly in tumours with secondary EGFR mutations
single-agent chemotherapy alone (Grade 2C). [16] following acquired resistance to EGFR inhibitors. [21]

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ June 15, 2016 ¦