treatments have moved much beyond the conventional surgery, radiotherapy and
chemotherapy. Drugs have been developed that target certain abnormal proteins
in the cancer cells and prevent their proliferation. The drugs target proteins
that are either excessive in the cancer cells, or are a result of a mutant gene
in the cancer cells. Such treatment, called targeted therapy, has the advantage
of a better effect on the cancer and lesser side effects on the other parts of
‘Non-small cell lung cancers show genetic changes during treatment with targeted therapy; therefore, combination targeted therapies or regular monitoring of the genetic changes during treatment may be required.’
has been assumed that a single gene is responsible for driving a particular
type of cancer. Treatment that is targeted against the particular gene is used
to treat the cancer.
targeted treatment is used to treat advanced non-small cell lung cancer
the patient responds
initially, but often the cancer recurs. To understand the reason for this, scientists studied the genes from the blood
samples from more than 2000 patients with advanced stage non-small cell lung
Among these, the cancers from 1122 patients had the mutated
epidermal growth factor receptor (EGRF) gene while the cancers from 944
patients did not have the abnormal gene. The scientists also studied the
genetic changes that took place in the cancer of a patient (who received
targeted therapy) sequentially on seven different occasions.
The scientists found that
The scientists therefore
suggest that non-small cell lung cancer is driven by multiple genes rather than
a single gene.
- More than
90 percent cases of the cancer had additional genes along with the EGRF
mutation that could be responsible for driving the cancer. The number of these mutations was even as high as 13.
in the TP53 gene were noted in more than 50 percent of the cancers. The TP53 gene controls the production of the p53
protein, a protein that suppresses cancer. Therefore mutations in the gene
have been associated with cancer.
- Other genetic mutations that were noted involved the
receptor tyrosine kinases, RAS-MAP kinase, PI3 kinase, Wnt/beta-catenin,
as well as in the genes involved in cell division, epigenetic
modifications, DNA repair, and cellular signaling pathways.
patients with an EGRF mutation who received targeted treatment developed
additional mutations that worsened the prognosis for the patients.
Thus, targeting a single gene is unlikely to be a complete
response since alternate genes may drive the cancer.
The exposure to only one
targeted drug could also result in resistance due to the possible development
of additional mutations
, which could make treatment even more difficult
and leave no options for the patient.
overcome such problems, the scientists
suggest targeting multiple proteins through a combination of targeted
treatments rather than using a single drug
. Another approach would be to
monitor the tumor genes during treatment of the cancer and change the treatment
according to the genetic changes.
About Non-small Cell Lung
Non-small cell lung
cancer is the most common type of lung cancer
accounting for around 80 to 85 percent of cases. It includes
adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, along with
other rarer cancers. Smoking
is a prominent risk factor for lung cancer
. Symptoms of the cancer may include
cough with blood-tinged sputum, chest pain, shortness of breath, hoarseness and
weight loss. The cancer can spread to distant organs like the liver, bone and
brain. Treatment is with surgery, radiation, chemotherapy, targeted therapies
Targeted therapies used for
the treatment of non-small cell lung cancers include the
- Angiogenesis inhibitors (drugs that prevent
proliferation of blood vessels) that include bevacizumab and ramucirumab
- Epidermal growth factor receptor (EGRF) inhibitors
- Drugs that target abnormal ALK protein that include
crizotinib, ceritinib, alectinib and brigatinib
- BRAF inhibitor dabrafenib
- MEK inhibitor trametinib.
The EGRF inhibitors include
- Erlotinib, afatinib and gefitinib
- EGRF inhibitors that also target cells with the T750M
mutation i.e. osimertinib
- EGRF inhibitor used in squamous cell non-small cell
lung cancer i.e. necitumumab.
- Blakely CM et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nature Genetics 2017; doi:10.1038/ng.3990
- Targeted Cancer Therapies - (https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet)