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case_images: Overview of patient disease progression.
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case_images: However, the patient refused this recommendation (Figure 1). To further validate our findings, using two representative non-small cell lung cancer cell lines, PC-9 and HCC827, we compared the expression levels after gene mutations (Figures S1 and S2, Supporting Information).
case_images: Comparison of liver imaging before and after tumor liver metastasis. In February 2023, PET/MRI results showed that the liver was in good condition and no metastatic tumors were found (in the left column). In May 2023, enhanced CT results indicated multiple liver metastases (in the third column from right to left). In July 2023, liver metastases gradually disappeared after a period of chemotherapy (in the second column from right to left). In February 2024, liver metastases completely disappeared (in the right column).
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case_images: She visited our department for another PET-CT examination, and the results were the same as before, with a new widespread bone metastasis throughout the body (Figure 2, left column). The enhanced CT showed multiple liver metastases (Figure 2, middle column with red arrow). To further validate our findings, using two representative non-small cell lung cancer cell lines, PC-9 and HCC827, we compared the expression levels after gene mutations (Figures S1 and S2, Supporting Information).
case_images: Time-course changes of various tumor markers in patients. Each panel represents the dynamic changes of a specific tumor marker over time. Top row, from left to right: The first panel shows the changes of NSE (Neuron-Specific Enolase). The second panel shows the changes of SCC (Squamous Cell Carcinoma Antigen). The third panel shows the changes of CYFRA 21-1 (Cytokeratin 19 Fragment). The fourth panel shows the changes of ProGRP (Pro-Gastrin-Releasing Peptide). The fifth panel shows the changes of AFP (Alpha-Fetoprotein). Bottom row, from left to right: The first panel shows the changes of CEA (Carcinoembryonic Antigen). The second panel shows the changes of CA19-9 (Carbohydrate Antigen 19-9). The third panel shows the changes of CA125 (Carbohydrate Antigen 125). The fourth panel shows the changes of CA15-3 (Carbohydrate Antigen 15-3). The fifth panel shows the changes of CA72-4 (Carbohydrate Antigen 72-4). The x-axis represents time, and the y-axis represents the concentration of the tumor markers.
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case_images: At the same time, AFP and CEA have slightly decreased compared to before, while still significantly higher than the normal range (Figure 3).
case_images: Correlation analysis of genes and biological pathways involved. (A-D) Immunohistochemical staining of EGFR, ARID1A, ZRSR2, TRKA (brown represents positive expression, and the darker the brown, the stronger the positive expression). (E) Differential expression protein domain analysis histogram. (F) Statistical map of KEGG pathway annotations for differentially expressed proteins (Top20).
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case_images: Only the protein expression in the exfoliated cells from pleural effusion in this case is presented (Figure 4A-D). Further functional testing analysis found that EGF domain is enriched, and differential proteins participate in multiple biological processes; protein interaction results confirm that multiple proteins on the PI3K signaling pathway can bind together in this case and exhibit strong biological functions in tumors (Figure 4H,I).
case_images: The correlations between individual gene and pathway score. (A) Protein interaction network structure diagram. (B) Immunohistochemical staining of PI3K and surface markers of immune cells (brown represents positive expression, and the darker the brown, the stronger the positive expression). (C-J) The correlations between individual gene and pathway score were analyzed with Spearman. The abscissa represents the distribution of the gene expression, and the ordinate represents the distribution of the pathway score. The density curve on the right represents the trend in distribution of pathway immune score, the upper density curve represents the trend in distribution of the gene expression. The value on the top represents the correlation p value, correlation coefficient and correlation calculation method.
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case_images: In addition, through in-depth discussion and analysis of differential proteins (all were compared with public data), it was found that the PI3K/mTOR signaling pathway plays an important role in this primary drug-resistant case (Figure 5A,B). We found that EGFR, ARID1A, NTRK1, and ZRSR2, acting alone or in concert, can accelerate the growth and spread of tumors and all be positively correlated with PI3K/AKT (Figure 5C-J).
case_images: The effect of different degrees of expression of individual genes on the action of Osimertinib. (A-C) Overexpression or knockdown of ARID1A, NTRK1, and ZRSR2 using plasmids, followed by treatment with Osimertinib to detect cell resistance. (D-F) Overexpression or knockdown of EGFR, NTRK1, and ZRSR2 using plasmids, followed by treatment with Osimertinib to detect PI3K-AKT in PC-9. (G-I) Overexpression or knockdown of EGFR, NTRK1, and ZRSR2 using plasmids, followed by treatment with Osimertinib to detect PI3K-AKT inHCC827.
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case_images: We found that the decreased expression of these genes can to some extent affect Osimertinib resistance (Figure 6A-C), thereby promoting the expression of PI3K-AKT (Figure 6D-F).