December 4, 2022

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Why is the brain metastases of lung cancer resistant to Osimertinib? 

Why is the brain metastases of lung cancer resistant to Osimertinib? 



 

Why is the brain metastases of lung cancer resistant to Osimertinib? 

 

Lung cancer is the most deadly tumor disease in the world today, and about 50% of patients have EGFR gene mutations [1, 2]. This part of the patients had a good response to the first- and second-generation EGFR-targeting tyrosine kinase inhibitor (TKI) treatment for the first time, but unsatisfactory, about 50% of the patients were treated with 9-14 Drug resistance develops after months [3, 4].

 

The emergence of the third-generation EGFR TKI drug Osimertinib extended the median disease-free survival of patients to 18.9 months, however, unfortunately, studies have shown that 20% of patients will develop central nervous system tumor metastasis, and ultimately affect The quality of life of patients and even shorten the survival period [5, 6].

Therefore, it is crucial to elucidate the mechanism by which CNS metastatic recurrence occurs in patients treated with Osimertinib.

 

Recently, a research team led by Anup Kumar Biswas and Swarnali Acharyya from Columbia University used immunodeficient mice to simulate brain metastases from lung cancer after Osimertinib treatment and found that lung cancer cells with brain metastases highly expressed S100A9 and promoted cells through the ALDH1A1-RA axis. survive .

They also confirmed that knockdown of related genes or the use of RAR inhibitors can effectively inhibit the growth of Osimertinib-resistant lung cancer cells in the brain [7] .

 

The important findings were recently published in the prestigious journal Cancer Discovery .

 

Why is the brain metastases of lung cancer resistant to Osimertinib? 

 

Next, let’s take a look at how the Biswas team carried out this research.

 

The Biswas team first used the human lung cancer cell line PC9-BrM3 with EGFR exon 19 deletion to construct an immunodeficient mouse brain metastasis model. Although Osimertinib treatment can effectively prolong the survival period without brain metastasis, all mice cannot escape brain metastasis after all. Even the doom of death , which is consistent with what happens to clinical patients after treatment.

 

Why is the brain metastases of lung cancer resistant to Osimertinib? 

Brain metastases of lung cancer cells after 237 days of Osimertinib treatment (left panel);

Brain metastasis-free survival in mice treated with Osimertinib (right panel)

 

To explore why, Biswas’ team isolated the aforementioned Osimertinib-treated mouse brain metastases (PC9-Tr-BrM), injected them into a new batch of mice, and then treated them with Osimertinib. As a result, they found that Osimertinib treatment accelerated brain tumor progression in PC9-Tr-BrM mice compared with mice injected with PC9-BrM. This shows that Osimertinib is helpless against lung cancer cells that have metastasized to the brain and developed drug resistance .

 

To explore the mechanism, the Biswas team performed quantitative mass spectrometry and transcriptomic analysis of PC9-BrM and PC9-Tr-BrM cells, and the results showed that S100A8 and S100A9 were highly expressed in PC9-Tr-BrM cells . Further functional experiments showed that lung cancer cells with high expression of S100A9 have stronger brain metastases , preliminarily showing that S100A9 is the “villain leader” that promotes brain metastasis of EGFR-mutant lung cancer cells.

 

Why is the brain metastases of lung cancer resistant to Osimertinib? 

S100A9 expression in brain metastatic lung cancer cells (Tr-BrM) and lung cancer cells (BrM) (left panel); brain fluorescence detection after S100A9 knockdown lung cancer cells and control cells were injected into mice (right panel)

 

To further explore the role of S100A9, Biswas’ team first sorted lung cancer cells with high and low S100A9 expression, and then injected these cells into different mice.

The results showed that the mice injected with high-expressing S100A9 lung cancer cells developed more severe brain metastases, confirming the identity of S100A9 as the “originator”, and suggesting that during Osimertinib treatment, the high-expressing S100A9 lung cancer cells could survive and serve as brain cells. Prepare for the transfer .

 

To explore how S100A9 affects the survival and proliferation of lung cancer cells, the Biswas team knocked down the expression of S100A9 in lung cancer cells and performed RNA sequencing analysis with control cells.

The results showed that ALDH1A1 expression was also significantly reduced in cells with low S100A9 expression. Subsequently, they confirmed that S100A9 promoted lung cancer cell survival and brain metastasis by upregulating the expression of ALDH1A1 .

 

 

Based on the above sequencing results, they also found that S100A9 can promote the activation of the retinoic acid (RA) metabolic pathway, and ALDH1A1, an important enzyme molecule of the RA pathway, is involved in S100A9-dependent lung cancer cell brain metastasis.

Therefore, they believe that RA pathway activation may be an important factor in promoting the proliferation of brain metastatic tumor cells after Osimertinib treatment . They then tested the above hypothesis using the RA receptor (RAR) inhibitor AGN-194310.

 

 

Why is the brain metastases of lung cancer resistant to Osimertinib? 

Two lung cancer cell lines (Tr-BrM) were injected into mice and treated with Osimertinib and RAR inhibitor, respectively, and the detection of brain metastases

 

Considering the heterogeneity of tumor cells during the actual development of tumors, the Biswas team injected unsorted PC9-BrM cells into mice to construct a brain metastasis model, and treated them with Osimertinib and RAR inhibitors in combination. Compared with the treatment group or the single drug group, the combination of the two can achieve the effect of removing residual tumor cells in the brain to the greatest extent .

 

After PC9-BrM mice were treated with Osimertinib and RAR inhibitor in vivo, brain tissue sections were stained for CK7

 

In addition to the above results, the Biswas team also experimentally demonstrated the specificity of the S100A9-ALDH1A1 axis for brain metastasis of lung cancer cells, that is, the survival and proliferation of lung cancer cells in lung tissue and metastatic to bone tissue does not depend on the S100A9-ALDH1A1 axis.

At the same time, they collected lung cancer tissue samples from patients with EGFR-mutant lung cancer and detected the expression of S100A9. The results found that the expression level of S100A9 in tumor cells was positively correlated with brain metastasis and shorter recurrence-free survival of patients .

 

In general, based on the phenomenon that 45% of EGFR-mutant lung cancer patients have brain metastases in clinical practice, and the current application of the third-generation drug Osimertinib, the Biswas team used immunodeficient mice to construct a lung cancer brain metastasis model and a series of experiments revealed Now , S100A9 is the “special liaison” of Osimertinib-resistant lung cancer cells for brain metastasis, and it promotes the survival and proliferation of tumor cells in the brain by regulating the ALDH1A1-RA axis .

 

Of course, this study has also been implemented at the level of diagnosis and treatment, suggesting that the expression of S100A9 in tumor cells before Osimertinib treatment can predict the risk of brain metastases after treatment, and the combined application of Osimertinib and RAR inhibitors can improve the clearance of brain metastatic tumor cells effectiveness.

 

 

 

 

 

 

 

 

 

references:

1. H. Sung, J. Ferlay, RL Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-49.

2.Y. Shi, JS Au, S. Thongprasert, S. Srinivasan, CM Tsai, MT Khoa, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014;9(2):154-62.

3.J. Rotow, TG Bivona. Understanding and targeting resistance mechanisms in NSCLC. Nat Rev Cancer. 2017;17(11):637-58.

4. JG Paez, PA Janne, JC Lee, S. Tracy, H. Greulich, S. Gabriel, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497 -500.

5. SS Ramalingam, J. Vansteenkiste, D. Planchard, BC Cho, JE Gray, Y. Ohe, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med. 2020;382(1) :41-50.

6.Z. Piotrowska, H. Isozaki, JK Lennerz, JF Gainor, IT Lennes, VW Zhu, et al. Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU- 667 for Acquired RET Fusion. Cancer Discov. 2018;8(12):1529-39.

7.AK Biswas, S. Han, Y. Tai, W. Ma, C. Coker, SA Quinn, et al. Targeting S100A9-ALDH1A1-retinoic acid signaling to suppress brain relapse in EGFR-mutant lung cancer. Cancer Discov. 2022 .

Why is the brain metastases of lung cancer resistant to Osimertinib? 

(source:internet, reference only)


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