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80% lung cancer is non-small cell lung cancer (Non-small cell lung cancer, NSCLC) , which is further divided into lung adenocarcinomas (Lung adenocarcinomas, LUADs) and lung squamous cell carcinomas (Lung squamous cell carcinomas, LUSCs) , the latter accounts for 20-30%, and the mortality rate is extremely high. In recent years, many breakthroughs have been made in the field of cancer treatment. For example, the emergence of inhibitors of the ligand (PD-1/PD-L1) has greatly improved the situation of NSCLC patients and significantly reduced the risk of recurrence in early patients. For diseases with local progression and unresectable, it can also help reduce distal metastasis and achieve better prognosis.
Unfortunately, most LUSC patients are at a high progression stage at the time of diagnosis, and even with PD-(L)1 inhibitors, the median overall survival rate (OS) was only 17.1 months. Although PD-L1 expression can be used as a benefit indicator of the therapy, it is not a perfect biomarker . By contrast, the driver mutations that are prevalent in LUADs are more predictive, yet they are almost none in LUSCs, and targeted therapies targeting prevalent abnormalities in LUSCs are very inefficient in clinical trials. The complex genomics of tumors, limited understanding of the mechanisms of oncogenic pathways and lack of representative mouse models have made the development of LUSCs drugs a long-standing challenge, with the lack of specific therapies and very few patient choices in high-progressive stages.
At this stage, therapies for LUSCs are mainly focused on appearance and metabolism. These new therapies can work in concert with immune checkpoint inhibitors. On October 20, 2022, Kwok Kin Wong from New York University's Grossman School of Medicine published an opinion article on Cancer Cell, outlining the research progress of LUSCs, summarizing the experience and lessons learned in past drug attempts, and looking forward to the future therapeutic direction.
Etiology and biological origins of squamous cell lung cancer
Biologically, compared with LUADs, LUSCs are more similar to squamous cell carcinoma (SCCs) (SCCs) , which originate from other esophagus, head and neck, and other parts. The molecular characteristics are reflected in high genetic mutations and chromosomal instability. LUSCs originate from basal-like stem cells (BSCs), , type 2 alveolar cells (AT2), and rod-shaped cells, and then differentiate under the combined action of transcription factors SOX2 and NKX2-1, as well as oncogenes, resulting in tumor plasticity and drug resistance.
LUSC therapeutic targets: The molecular events that recurred in
were key oncogenic factors in LUSC and can be used as potential drug targets. However, due to the extremely high mutation load in LUSC (8.1/Mb) , it is difficult for us to distinguish between bystander genes and mutant genes. In this case, drugs targeting receptor tyrosine kinases (receptor tyrosine kinases, RTKs) , signal transduction, cell cycle checkpoint , etc. were used.
is first a kinase inhibitor. afatinib is currently the only single agent approved for LUSCs, and nyxitozumab combined with chemotherapy is one of the few approved targeted therapies. However, the EGFR-based method is highly toxic and the ERBB-based therapy is not significant. Another RTK is FGFR, but its inhibitors nindanib and dovetinib are of little effect. The oncogenic levels of DDR2 mutations may be very low, and no relevant targeted drugs have been approved or used in clinical trials. The above examples of RTK inhibitors show that the selection of specific biomarkers is very important and that true oncogenic driver genes are identified.
The second largest class of drugs targeted signal transduction. RTK signaling generally regulates the RAS-RAF-MEK and PI3K protein kinase pathways, but related studies have not achieved good results.The effect of RAS mutation on LUSC tumor growth is unknown, and patients may not necessarily benefit from related targeted mutation therapy. The combination of MEK inhibitor semetinib and chemotherapy failed in the Phase III clinical trial. The mutation that inhibits PIK3CA in PI3K signal was negative in clinical trials and was highly toxic. The above two points are explained: The signal transducing pathways are connected in series with (Crosstalk) is very common, and there is a cascade effect, so it is not enough to target one of them; signal transduction inhibitors damage normal cell biology processes, which often brings great toxicity.
The third type of drugs target the cell cycle. The cell cycle is located downstream of the oncogenic signaling pathway and is an attractive therapeutic target. CDKN2A inactivation or HRB1 deletion will cause the cell cycle to lose control. The CDK4/6 inhibitor developed based on this has little effect in LUSC, even if the patient expresses the corresponding molecular marker CDK4/6 inhibitor has little effect in LUSC, even if the patient expresses the corresponding molecular marker (CDKN2A inactivated mutation or CDK4, CCND1/2/3 amplification) , the overall response is also very low (only 6%) . Proteomics studies show that this pathway is very complex and we need to understand further to identify the correct targets and biomarkers.
LUSC therapeutic targets: Now,
In addition to the genome, the factors that affect squamous differentiation and tumor survival also include the epitome and metabolic groups. Epilogic therapies regulate oncogenes and related pathways by influencing transcriptional programming, causing metabolic disorders, which can be used in drug development. In
LUSCs, global DNA hypomethylation enables transcriptional activation of oncogenes, and loci-specific hypermethylation silencing tumor suppressor genes, thereby increasing tumor heterogeneity and plasticity. Epilogic therapies in the past were generally inhibiting DNA methyltransferase (DNMT1) or histone deacetylation enzyme (HDAC) , but they performed poorly due to their high toxicity and low effects. Nowadays, second-generation drugs select populations based on biomarkers and work in concert with other therapies to cope with tumor resistance. The chromatin regulators LSD1 and EZH2 of the transcription factor SOX2 are very potential drug targets. Inhibition of LSD1 reduces oncogenic potential and promotes cell differentiation. The increase of EZH2 is related to squamous transformation. Both inhibitors are currently in clinical trials. Other regulators such as KMT2D and NSD3 also have drug development prospects. The former has mutations in 22% of LUSCs, and its deletion leads to loss of tumor suppressor function and metabolic defects, while the latter inhibitors hinder tumor growth. The selection pressure of the therapy can lead to squamous transformation, and LSD1 and EZH2 inhibitor treatments make prostate tumors responsive to androgen inhibitory therapy, suggesting that apparent therapies help address targeted therapies resistance to squamous transformation lung cancer.
cell metabolism disorder is a major feature of cancer. LUSCs highly express GLUT1 glucose transporter, relying on glycolysis . The KEAP1-NRF2 pathway is an important regulator of oxidative stress response. Under normal circumstances, KEAP1 ubiquitinates NRF2 to degrade it, while under stress conditions, KEAP1 activity is reduced, and NRF2-related genes are transcribed, resisting reactive oxygen species (ROS) and regulating immune response. KEAP1 shows functional deletion mutations in LUADs, and NFE2L2 shows functional acquired mutations in LUSCs. Both are mutually exclusive and both lead to continuous expression of NRF2 signals, which is very unfavorable for advanced patients and will lead to drug detoxification and drug resistance. A more profound impact is metabolic reprogramming, and the availability of glutamine in tricarboxylic acid cycle is reduced, forming a metabolic bottleneck. The metabolic environments of different mutated LUAD mice are significantly different, and finding the correct biomarkers is very important for targeting metabolic abnormalities.In addition, since glutamine is necessary for CD8+ T cell activation, it is important to evaluate the effect of PD-(L)1 inhibitors on glutamine response.
LUSC therapeutic targets: In the future,
identified robust biomarkers are very necessary for the development of effective LUSCs therapies. Patients are encouraged to undergo NGS and use a combination of multigenes to guide therapies. In immunotherapy, biomarkers for comprehensive evaluation of tumor immune microenvironment (TIME) (TIME) are needed. In addition, finer subclassifications can also help improve the success rate of therapy.
Combination therapy based on tumor biology can also improve the effectiveness of treatment. Currently, most of them are combined with immune checkpoint inhibitors, which requires a comprehensive understanding of the molecular mechanisms shaping of TIME. Such as the combination of epithelial therapy and chemotherapy, targeted therapy, and immunotherapy, more research is needed to understand the risks and challenges, as well as appropriate biomarker selection.
To sum up, LUSCs have many similarities with SCCs in other parts, and their drug research will have a profound impact on the treatment of other squamous cell carcinoma . Although drug exploration of LUSCs has not yet achieved good results, new approaches to combining epigenetic and metabolism are promising. Furthermore, LUSC genomic complexity may be beneficial for immunotherapy, especially when combined with biomarker-oriented targeted therapy.
original link:
https://doi.org/10.1016/j.ccell.2022.09.018
Platformer: Eleven
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