Non-small cell lung cancer (NSCLC): emerging therapeutic targets and therapeutic drugs

← Swipe left and right to view, click [Read the original text] to learn more → [Author: Zhang Hu] Lung cancer accounts for 11.
6% of all malignant tumors.
It is not only the most common malignant tumor in the world, but also the most common cause of cancer-related deaths (accounting for 18.
5%)
.

An estimated 2.
9 million new lung cancer cases were diagnosed in 2018
.

An estimated 1.
6 million people die from lung cancer each year
.

With global population growth, aging and changing life>
.

Lung malignant tumor is the main cause of death from cancer in men, and it has surpassed breast cancer in developed countries
.

Factors that contribute to lung cancer include smoking, use of tobacco products, asbestos exposure, environmental pollutants (including radon), and chronic respiratory infections
.

These malignant tumors tend to occur in aggressive and metastatic diseases, and their origin and tumor characteristics are highly heterogeneous
.

All types of lung cancer can invade locally, causing multifocal lesions originating from the lobe, spreading to the entire lung, or invading the mediastinum or the contralateral lung
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The involvement of lymph nodes associated with mediastinal invasion can cause local space-occupying effects, leading to pathological reactions in the esophagus, veins, and trachea
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Then there are further metastases such as brain, bone or liver
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Lung cancer is divided into two categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)
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NSCLC is the most common, accounting for approximately 85% of all lung cancer cases in the United States and Europe, and has the highest mortality rate
.

NSCLC can be divided into adenocarcinoma, squamous cell carcinoma, and large cell lung cancer
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Adenocarcinoma occurs in the peripheral bronchus and progresses through lobular atelectasis and pneumonia; it accounts for 40% of all lung cancers
.

Squamous cell carcinoma occurs in the main bronchus and progresses to the carina and above, accounting for 25-30% of all lung cancers
.

Large cell carcinoma, which accounts for 10% of lung cancers, occurs in the proximal thoracic cavity and tends to infiltrate the mediastinum at an early stage
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Among them, 10-15% of small cell lung cancers are particularly aggressive
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They are derived from lung hormone cells and are usually manifested as a large number of dedifferentiated central mediastinal tumors, and lymphatic spread appears early, usually before bronchial infiltration
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Due to its unique histology and spreading methods, SCLC can be divided into two types, limited type (limited to hemithorax or origin, mediastinal or supraclavicular lymph nodes) and extensive type (spreading beyond the supraclavicular area)
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NSCLC uses TNM staging for classification
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The staging may be related to the pre-treatment clinical staging, pathological staging, post-operative staging, post-neo-adjuvant therapy or post-neo-adjuvant therapy and surgical staging
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The clinical staging before treatment is determined by a combination of medical history, clinical examination, serology, diagnostic imaging, endoscopic evaluation, diagnostic surgical evaluation, and pathology
.

For SCLC and NSCLC, the accurate staging and scoring of the patient's physical status is critical to the prognosis and treatment plan
.

Molecular targeted therapy According to the clinical practice guidelines of the American Society of Clinical Oncology and the European Society of Medical Oncology, platinum-containing dual-agent chemotherapy is the standard first-line treatment for patients with advanced NSCLC
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However, the curative effect of these patients is not good, the mortality rate is significant, and the combination of tumor mutations has led to the progress of targeted therapy
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Targeting EGFR has currently found several gene mutations in NSCLC
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Epidermal growth factor receptor (EGFR) mutations are found in 10-15% of cases in the United States, and up to 35% in East Asia
.

EGFR mutations play a role in the proliferation and survival of cancer cells, making them suitable targets for blocking (Figure 1)
.

EGFR tyrosine kinase inhibitors (TKI) (EGFR-TKI) can be treated by targeted mutations.
Five TKIs are the first-line treatment options for EGFR+NSCLC: erlotinib, gefitinib, afatinib, osimertinib and dacomitinib
.

Compared with conventional chemotherapy, these drugs can improve the progression-free survival (PFS) and overall survival (OS) of this patient group, and there are fewer adverse events of grade 3 or above
.

Figure 1.
EGFR-mediated tumor survival, proliferation and movement pathways and the mechanism of action of EGFR-TKI target ALK rearrangement.
In previous studies, mutations associated with the progression of NSCLC include ALK, K-RAS, BRAF, AKT1, PIK3CA, Mutations in the MET and HER2 pathways
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These oncogenes rely on the phosphorylation of tyrosine, serine and threonine receptors, which in turn act on various growth and mitotic pathways
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The chromosomal rearrangement of anaplastic lymphoma kinase gene (ALK) has been shown to be an effective target for genome therapy
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With the widespread application of these targeted therapies in the past decade, the survival time of ALK rearranged NSCLC has been significantly improved
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ALK rearrangement is present in 3-7% or NSCLC, and is related to adenocarcinoma, younger patients, and no history of smoking (Figure 2)
.

Figure 2.
ALK-mediated tumor survival, growth and proliferation pathways and the mechanism of action of ALK-TKI targeting KRAS G12C mutation KRAS site mutation is a new target for NSCLC therapy
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KRAS mutations are common in epithelial, colorectal, pancreatic, and lung adenocarcinomas.
KRAS mutations have been observed in 90% of pancreatic masses, more than 40% of colon cancer cases, and 13% of lung cancer cases (Figure 3)
.

At present, the most significant clinical mutation is the G to C transition of gene codon 12 or 13, named KRAS G12C mutation
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20-50% of lung adenocarcinomas carry KRAS mutations, and more than 10% of specific KRAS G12C mutations
.

Figure 3.
KRAS G12C-mediated tumor proliferation pathway and the mechanism of action of KRAS G12C inhibitors Although therapies targeting EGFR and ALK have been developed and proven effective, although the therapeutic effects are different, there are few options for KRAS mutations
.

The main reasons for the failure are the high affinity of KRAS G12C to GTP/GDP and the difficulty in developing inhibitors of binding pockets
.

Regardless of the tumor's EGFR status, therapies targeting EGFR are largely unsuccessful.
This may be due to the continuous activation of the Raf-MEK-ERK pathway downstream of EGFR by KRAS
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Currently, several ongoing trials have shown promising results for direct inhibition of KRAS G12C
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Other TKI targets In fact, 2-4% of NSCLC patients have BRAF oncogene mutations, of which about half are V600E mutations
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In Europe, dabrafenib plus trametinib has been approved for the treatment of patients with metastatic NSCLC with BRAF V600E mutation
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RCT and real-world retrospective data show that the combination therapy has comparable efficacy and safety characteristics
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1%-4% of NSCLC tumors carry HER2 mutations, but there is currently no HER2 targeted therapy for NSCLC
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In a recent phase II trial conducted in 18 enrolled patients, it was confirmed that patients with stage IIIb/IV NSCLC received afatinib as a targeted therapy.
The results showed no benefit in terms of PFS, OS, or safety characteristics.
The study was discontinued due to poor efficacy and slow recruitment
.

The poor survival rate of NSCLC immunotherapy and TKI therapy and safety issues have stimulated the progress of targeted immunotherapy
.

For example, most patients with NSCLC may have subclinical metastasis at the time of diagnosis, while patients with chronic obstructive pulmonary disease have found tumor cells in the bloodstream several years before the clinically obvious disease
.

However, according to the work of Bobbio and Alifano, most patients with early-stage NSCLC did not experience clinically significant disease recurrence after radical resection
.

This may mean that removing most of the tumor burden can allow the host's immune system to fully restore function to "clear" the remaining tumor cells in the distance
.

The proliferative stage tumors are resistant to the above-mentioned immune surveillance.
They can create an immunosuppressive microenvironment to help escape NK cells, CD4 + T cells, CD8 + T cells and macrophages
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Immunotherapy usually attempts to enhance the response of anti-tumor immune cells during the elimination phase
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Currently, Immune Checkpoint Inhibitor (ICI) is the most studied immunotherapy for NSCLC
.

The immune checkpoint pathway involving the PD-1 receptor and its ligands PDL-1 and PDL-2 has always been a key therapeutic target
.

Figure 4.
Schematic diagram of immune checkpoint inhibitor mechanism.
ICI suppresses by targeting the following targets, including cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death protein 1 (PD-1) or programmed cell death Protein ligand-1 (PDL-1)
.

Some ICIs have shown improved outcomes in clinical trials
.

A meta-analysis comparing chemotherapy alone or first-line treatment with ICI in a total of 8081 patients with advanced NSCLC showed that combined ICI can improve tumor remission
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PFS and OS have also improved
.

In contrast, combined immunotherapy resulted in higher grade 3-5 toxicity
.

In patients with positive PDL-1 expression or high tumor mutational burden (TMB), a comparison of immunotherapy and chemotherapy alone showed no difference in grade 3-5 toxicity, OS and PFS
.

Table 1.
Summary of currently available NSCLC antibodies and vaccines.
Table 2.
Summary of ongoing clinical trials.
Despite the ongoing use of chemotherapy, targeted molecular therapy, surgical resection and radiation therapy, non-small cell lung cancer (NSCLC) is still very popular.
It is common, and the morbidity and mortality are high
.

In recent years, immunotherapy has become an effective, safe and universal treatment for these patients
.

Its applications range from first-line treatment to improvement of quality of life
.

With the continuous emergence of optimized immunotherapy programs for NSCLC patients, the quality of life of NSCLC patients will also improve, and the future can be expected! References: Singh T, Fatehi Hassanabad M, Fatehi Hassanabad A.
Non-small cell lung cancer: Emerging molecular targeted and immunotherapeutic agents.
Biochim Biophys Acta Rev Cancer.
2021 Dec;1876(2):188636.
doi: 10.
1016/j.
bbcan.
2021.
188636.
Epub 2021 Oct 14.
PMID: 34655692.
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