Targeted drugs for the driving gene of lung squamous cell carcinoma are finally on the scene!

Non-small cell lung cancer accounts for up to 80% of lung cancer, which is the most important subtype of
lung cancer.
Non-small cell lung cancer is also subdivided into squamous cell carcinoma, lung adenocarcinoma, etc
.
At present, for the treatment of lung adenocarcinoma, the corresponding targeted drugs can be used through genetic testing, so what about lung squamous cell carcinoma? Lung squamous cell carcinoma does not have high-frequency driver gene mutations, is it necessary to conduct genetic testing to find targeted drugs, or is it better to use chemotherapy in combination with immunotherapy directly? A recent study published in the journal JTO gives us a clear answer
.

Current status of treatment of squamous cell carcinoma

Lung squamous cell carcinoma accounts for about 15% of all lung cancers worldwide, with about 315,000 new cases
each year.
At present, the prognosis of lung squamous cell carcinoma is relatively poor, with a median overall survival of only 18 months
.
Because lung squamous cell carcinoma does not have high-frequency driver gene mutations, targeted therapy for lung squamous cell carcinoma has been difficult for a long time
.

Researchers have studied the driver genes of lung squamous cell carcinoma, such as FGFR1 gene amplification, PIK3CA mutation, PTEN gene deletion, CCND1 gene amplification, CDKN2A gene deletion, etc.
, these gene mutations account for about 50%, but the drug treatment response rate is only 10%, and the median progression-free survival is 2 to 3 months
.

The KEAP1 gene, or NFE2L2 gene, is present in 20 to 30 percent of lung squamous cell carcinomas, and scientists have found that activating mutations in the NFE2L2 gene have the potential to
drive tumorigenesis.
The NFE2L2 gene encodes for the NRF2 protein, and the protein encoded by the KEAP1 gene is upstream of the NRF2 gene, and the two genes affect a signaling pathway
.

In order to verify whether there is a targeted therapy for these two gene mutations, the researchers used the TORC1/2 inhibitor TAK-228, and the results confirmed that it does have a good effect on the NFE2L2 gene and has therapeutic potential
in the treatment of advanced lung squamous cell carcinoma.

TAK-228, a targeted new drug targeting the NFE2L2 gene

In this phase II clinical study, the median age of patients was 70 years, and most had a history of
smoking.
The patient has received more than two previous systemic treatments
.
Most patients use platinum-based chemotherapy first-line and immunotherapy
second-line.
After second-line resistance, there is no good treatment option to
choose from.

Patients were divided into three groups, and the genetic mutations were:

1. 12 patients with lung squamous cell carcinoma with NFE2L2 gene mutation;

2. 6 lung squamous cell carcinoma patients with KEAP1 gene mutation;

3. Patients
   with non-small cell lung cancer with a mutation in the KRAS gene, but also a mutation in the NFE2L2 gene or a mutation in the KEAP1 gene.
   

For three groups of patients, TAK-228, a TORC1/2 inhibitor
, was used simultaneously.
The results of the study showed that the drug worked best
in patients with lung squamous cell carcinoma with NFE2L2 gene mutations.

Patients with lung squamous cell carcinoma have a mutation in the NFE2L2 gene, and treatment with TAK-228 can achieve a 25% treatment response rate and a median progression-free survival of 8.
9 months
.

Genetic variants and responses to treatment in patients participating in clinical studies

In this clinical trial, some patients had both PIK3CA and KEAP1 or NFE2L2 mutations, but the treatment results were different
.
As shown
in the image above.

• A patient with both a KEAP1 mutation and a PIK3CA mutation achieved partial remission
  in a clinical trial with reduced lesions.
  But other patients don't
  .
  

• Patients with both NFE2L2 and PIK3CA amplification mutations showed little change
  in treatment.
  

• Patients with both KEAP1 and PIK3CA mutations, as well as PTEN mutations, also had no shrinkage
  .
  

Therefore, if the patient's driver gene is scattered and there are multiple gene mutations, the efficacy of TAK-228 treatment is not predictable
.

epilogue

For the NFE2L2 gene, most tumor gene testing packages are not covered, and we often use the driver gene package of lung adenocarcinoma to detect lung squamous cell carcinoma, which often leads to missed detection and cannot find the true driver gene mutation of
the tumor.
Only by finding the driver gene of the tumor can the corresponding targeted therapy opportunity
be analyzed.

Patients with lung squamous cell carcinoma have a certain probability of having mutations in the EGFR and ALK genes, but the probability of mutation is much lower than that of lung adenocarcinoma
.
Some patients use second-generation EGFR-targeted drugs directly without any genetic testing, but the effect of the drug will be short
.

Through the above-mentioned small clinical trials, it is believed that lung squamous cell carcinoma will also usher in the opportunity
of targeted therapy.
Regarding the TAK-228 drug described in this article, there will definitely be opportunities for
clinical trials in the later stage.
Patients in need should pay attention to the degree of cancer, send your genetic test report to the details of cancer medical consultation, and learn more professional diagnosis and treatment information
.

Pay attention to the degree of cancer, take every step of cancer prevention and anti-cancer!

References: Paik PK, et al.
, Targeting NFE2L2/ KEAP1 mutations in advanced non-small cell lung cancer with the TORC1/2 inhibitor TAK-228, Journal of Thoracic Oncology (2022)

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