Targeted Therapy for Lung Cancer

Treatment of patients with metastatic small cell lung cancer (NSCLC) is traditionally based on cytostatic therapy.

Chemotherapy destroys the targeted cells, relieves symptoms, improves quality of life and extends life expectancy in some patients with NSCLC.

Researchers have been studying meticulously about the development of lung cancer cells; they have developed newer drugs that specifically target changes in cancerous lung cells. These targeted therapy drugs work differently from standard chemotherapy; they work when chemo drugs don’t have an effect, and they have fewer side effects.

Targeted therapy drugs can be appointed in addition to chemotherapy or by themselves.

This article summarizes the results of several research studies on screening of mutations in patients with NSCLC, as well as the efficacy of targeted therapy for lung cancer, appointed on the basis of the screening results.

Understanding the complex mechanisms responsible for tumor formation in NSCLC and other neoplastic diseases has allowed developing drugs with selective action on specific processes in malignant cells.

It is believed that these drugs (targeted drugs) are relatively harmless to healthy cells, but are extremely effective in fighting cancer.

Most targeted agents are appointed in tablet form and are tyrosine kinase inhibitors. There are drugs are available in the form of intravenous injections as well. They belong to the category of monoclonal antibodies or small molecule compounds.

The traditional approach to the treatment of lung cancer in Israel has undergone significant changes due to the opening of the oncogenic activity of tyrosine kinase family of enzymes, the identification of mutations in the epidermal growth factor receptor (EFGR) and translocation gene ALK, coding for the synthesis of anaplastic lymphoma kinase.

The research aims for the identification of other biomarkers of cancerous cells and the development of appropriate targeted agents conducted intensively. As expected, in the near future the results will move to phase III clinical trials of new targeted drugs intended for the treatment of NSCLC.

Theoretical Substantiation of Targeted Therapy for Lung Cancer

Most biomarkers that determine the effectiveness of targeted therapy for non-small cell lung cancer are genomic abnormalities that are called driver mutations (mutation – “driver”).

Driver mutations are present in cancer cells and affect the genes encoding the synthesis of proteins, whose presence in the cell is a prerequisite for growth and survival.

In NSCLC cells a number of other mutations have also been identified, which do not play a significant role in maintaining the tumorigenic phenotype; these mutations are called secondary, or “passengers”.

Driver mutations are not found in other cells of the body (non-cancerous) and are usually exclusive: in tumor cells, there is only one kind of driver mutations.

Driver mutations have a transformative nature that is spearheading a normal cell for malignancy. Moreover, driver mutations play the role of a biological “switch”; they perpetuate the cancer cell phenotype, excluding it from the processes of biological regulation.

Thus, driver mutations can be considered as reliable biomarkers within the selection of candidates for the appointment of targeted therapy. Moreover, a driver mutation represents an ideal target for targeted therapy as the survival of the cancer cell depends on the activity of driver mutations, which “turn off” other mechanisms of biological regulation.

In NSCLC and other cancers, identification of driver mutations in the individual patient and consequently, the appointment of adequate targeted therapy to optimize the therapeutic effect, in most cases, allow you to reduce toxicity. The identification of driver mutations can and should be viewed as an integral part of the process of diagnosis of patients with NSCLC. On the basis of these results, we can make a decision on the appointment of a patient for standard chemotherapy (in the absence of driver mutations) or targeted therapy.

Driver Mutations Screening Techniques

Currently, there is no standard method for the identification of driver mutations.

For this purpose may be used:

Genome sequencing, both classical and automated, which is the most complex and expensive method of testing
Identification of specific alleles on the amplified DNA; a cheaper and faster method. However, it only allows us to identify known mutations and is not able to diagnose previously unknown anomalies
Mass spectrometry; also identifies only mutations previously known
Hybridization Fluorescence in situ (FISH). Used for identification of translocations and gene amplifications detecting specific sequences in the genome and their localization

For testing purposes, it is advisable to use a method that has the following qualities:

• An ability to work with the available biological material samples (blocks of formalin, paraffin-embedded, and the likes)
• Inexpensive
• A Relatively fast process execution
• Partial automation

Multiplex Genotyping

Multiplex genotyping allows us to perform a parallel investigation of several loci, based on a single biological sample without the need of a series of successive tests.

Thus, within the multiplex genotyping it is possible to work with a small volume of histopathological specimens of tumor tissue and greatly enhance the processing results.

Multiplex genotyping is an effective method and can be regarded as a practical tool in the planning of further therapy.

As part of the test screening for NSCLC, 552 patients underwent the procedure of multiplex genotyping, in which tumor samples were subjected to examination for the presence of 50 mutations in key genes of NSCLC. In 51% of patients, the presence of at least one mutation was observed. The most common mutations include KRAS (24%), EGFR (13%), PIK3CA (4%) and the translocation gene ALK (5%).

Genotypes of Non-Small Cell Lung Cancer

The driver mutations listed below are the most characteristic for patients with small-cell lung cancer and represent a target for the currently existing targeted therapies (they have gone past clinical testing phase and are in phase III clinical trials).

Indications for the use of targeted therapy can be one of the driver mutations appearing in the list. In the absence of adequate targeted therapy or the patient’s inability to participate in the program of clinical trials of targeted funds, it is advisable to use standard cytotoxic therapy.

EGFR

Epidermal growth factor receptor (EGFR) is a protein found on the surface of cells. It normally helps the cells to grow and divide. Some NSCLC cells have too much EGFR, which causes them to grow faster.

EGFR gene mutations are present in approximately 15% of patients with NSCLC in the United States. They are more common with non-smokers. In patients of Asian origin, the mutation is considerably higher and can reach 62%.

In patients with advanced lung cancer with the presence of EGFR, there is a favorable prognostic sign, as it involves tumor susceptibility to tyrosine kinase inhibitors: Erlotinib and Afatinib.

ALK translocation

The ALK gene rearrangement produces an abnormal ALK protein that causes the cells to grow and spread.

According to research conducted in the United States, the tyrosine kinase ALK gene translocation is observed in approximately 4% of patients with non-small cell adenocarcinoma. They are prevalent in younger patients and in non-smokers or in light smokers. Crizotinib is the drug given to those patients to block the abnormal ALK protein.

In the vast majority of cases, KRAS mutations are found in tumors with EGFR or ALK.

KRAS mutations are found in tumors from both former or current smokers and non-smokers.

Numerous attempts to identify specific inhibitors of the K-RAS have been unsuccessful. At the moment, the possibility of exposure to effectors activated KRAS:

Preclinical lab studies on genetically engineered mice demonstrated that tumors containing exclusively K-RAS mutations are more susceptible to combination therapy with docetaxel, and selumetinib. At the same time, the combination of KRAS and p53 is characterized by moderate sensitivity and KRAS and LBK1 – resistance. Evidently, the effectiveness of treatment, in this case, is determined by the presence of mutations in complex-“passengers”.
Inhibitor of MEK – trametinib. A Positive effect of trametinib has been recorded in patients with NSCLC, but convincing evidence of its connection with the presence of KRAS mutations was not available
For patients who were unable to participate in clinical trials, treatment recommendations for small cell lung cancer with K-RAS are the same as for patients with non-small cell adenocarcinoma of an unknown genotype.

HER2

HER2 (ERBB2) – receptor tyrosine kinase group EFGR. Mutations in the gene HER2 have been reported in 1-2% of patients with NSCLC. They usually represent the insertional mutation in exon (at least – point mutations). These tumors are non-small cell type mutations and are more common in women, as well as in non-smokers.

HER2 amplification does not belong to the category of driver mutations, and previous studies showed no clinical effect of trastuzumab in patients with amplification of HER2.

A new series of trials has recorded partially positive effects in patients receiving combined treatment with trastuzumab and cytostatic agents, and in the group treated with afatinib – EGFR/HER2 tyrosine kinase inhibitor.

A partly positive reaction was observed in patients with NSCLC and HER2 mutations during therapy neratinibom (pan-HER2 inhibitor) and temsirolimus (mTOR inhibitor).

BRAF

BRAF encodes a protein synthesis B-RAF, which is a mediator of KRAS, activating the MAP-kinase cascade. BRAF mutations are present in 1-3% of patients with NSCLC, especially in smokers and patients with non-small cell adenocarcinoma. Activation of B-RAF mutation was observed at position 15 of exon V600 (a similar mutation is observed in patients with melanoma) or at other sites.

As the data collected during Phase 1-2 clinical trials, a partly positive response was seen in patients with small-cell lung cancer and mutation V600E, treated with dabrafenibom – an inhibitor of BRAF. The side effects of therapy dabrafenibom NSCLC were similar to responses observed in melanoma patients receiving similar treatment.

Another treatment strategy is to use the MEK inhibitors of tyrosine kinase (see “Mutations RAS»).

Expression of MET

MET – a tyrosine kinase receptor for the hepatocyte growth factor. MET mutations in patients with NSCLC are rare and their clinical significance has been insufficiently studied. At the same time, MET overexpression is noted in 25-75% of cases of NSCLC and, as a rule, is a poor prognostic sign.

Positive effects of targeted therapy of lung cancer were reported in clinical trials. Preparations:

Tivatinib – MET tyrosine kinase inhibitor
Onartuzumab in combination with erlotinib. Onartuzumab – a monovalent antibody that selectively binds to the extracellular domain of MET
Krizotinib – a drug that blocks ALK and ROS1, has the potential to MET inhibition in patients with MET-amplifications

FGFR1 amplification

Fibroblast Growth Factor Receptor (FGFR1) – a membrane receptor of tyrosine kinase that participates in the processes of cell viability and proliferation. FGFR1 amplification is present in 13-25% of patients with squamous cell carcinoma of the lung. They are more common in smokers and are associated with poor prognosis.

Targeted drugs are in development. A case of tumor regression in FGFR1tirokinazy inhibitor therapy is – drug BGJ398.

A mutation in the β-catenin

Synthesis of β-catenin, encoded by the gene CTNNB1. Β-catenin, a protein conjugated to APC protein, plays an important role in the regulation of epithelial cell growth. CTNNB Mutations detected in 2% of patients with NSCLC, in particular, EFGR-positive tumors, and cause the development of resistance to EFGR inhibitors. Mutations are classified as a passenger. They are present in a complex way with a variety of driver mutations, so their clinical importance and effectiveness in targeted therapies is currently considered invalid.

RET translocations

RET gene encodes a membrane receptor tyrosine kinase. Translocation between RET and CCDC6, KIF5B, NCOA4 observed in approximately 1% of patients with NSCLC as adenocarcinoma & squamous cell carcinoma. Mutations are usually present in younger patients and nonsmokers (never smoked in the past).

RET tyrosine kinase inhibitors include vandetanib, sorafenib, and sunitinib. However, large-scale clinical trials have not shown an increase in survival in patients treated with targeted therapy of this type. Described isolated cases of positive reactions have been recorded in patients NSCLC treated with RET translocations therapy vandetanibom or kabozantinibom.

DDR2

DDR2 gene encodes a membrane receptor tyrosine kinase. The mutation resulting in the activation of the receptor is observed in 4% of patients with NSCLC with squamous cell carcinoma of the lung. A case of a positive reaction is combination therapy with erlotinib and dasatinib.

MEK1

The gene encodes a protein synthesis MAP21K MEK1, located in the signal circuit at the position following the RAF. MAP21K mutations are observed in approximately 1% of patients with non- small cell lung adenocarcinomas. The clinical significance of this category of mutations and the effectiveness of targeted therapy MEK inhibitors or ERK are under study.

Conclusion

Understanding the molecular mechanisms underlying the processes of malignancy in patients with NSCLC, allows us to develop a number of targeted therapies that are able to execute a selection between normal and cancerous cells.

The most effective biomarkers that determine the effectiveness of targeted therapies are mutations drivers – somatic genetic abnormalities.

Driver mutations are present in the genome of cancer cells and disrupt the synthesis of proteins, which play a critical role in the growth and survival of cells. Quite often driver oncogenic mutations fixed phenotype cells, resulting in the fact that the cell is excluded from the processes of biological regulation, and its continued survival is determined by signals from the driver.

The most well-known biomarkers are mutations and translocations EFGR & ALK. The identification of biomarkers of data formed the basis for the development of highly targeted funds, the use of which led to significant successes in the treatment of lung cancer. The effectiveness of targeted cancer therapy is a stimulus for further research in this direction: Driver identifies other genetic abnormalities and drug development, appropriate to the particular type of mutation.