Research Highlights
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Research Spotlight
Triple-negative breast cancer (TNBC) is challenging, making up 15–20% of all breast cancer cases. This study examined how certain drugs, like lapatinib (a dual tyrosine kinase inhibitor targeting EGFR and Her2) and berberine (a plant-based compound), affect TNBC cells. We found that lapatinib activates a protein called Akt in MDA-MB231 TNBC cells, which could contribute to the cancer's resistance to treatment. We also studied the genetic profiles of different TNBC cell lines and patients. Interestingly, lapatinib and berberine enhanced Akt activity in TNBC cells, making them more resistant to treatment. These findings suggest that these drugs may not be effective in treating TNBC and could even make the cancer more resistant to therapy.
Our recent research analyzed the gene expression of specific cancer-promoting proteins in ten different triple-negative breast cancer (TNBC) cell lines and TNBC patients, utilizing GEO and TCGA databases. Our current findings have highlighted that the majority of the chosen cell lines, including MDA-MB231 and TNBC patients, exhibit decreased levels of AKT1, PIK3CA, PTEN, and EGFR genes while showing increased levels of KRAS and DNMTs. These observations suggest that these genes are associated with the invasive nature of TNBC.
RNA-seq analysis of resistant triple-negative breast cancer cells treated with lapatinib and berberine
Lapatinib
and berberine shows upregulation of oncogenic PI3K/Akt signaling
Triple-negative breast cancer (TNBC) is challenging, making up 15–20% of all breast cancer cases. This study examined how certain drugs, like lapatinib (a dual tyrosine kinase inhibitor targeting EGFR and Her2) and berberine (a plant-based compound), affect TNBC cells. We found that lapatinib activates a protein called Akt in MDA-MB231 TNBC cells, which could contribute to the cancer's resistance to treatment. We also studied the genetic profiles of different TNBC cell lines and patients. Interestingly, lapatinib and berberine enhanced Akt activity in TNBC cells, making them more resistant to treatment. These findings suggest that these drugs may not be effective in treating TNBC and could even make the cancer more resistant to therapy.
Immunoblot analysis after 48-h treatment. (Source)
Our recent research analyzed the gene expression of specific cancer-promoting proteins in ten different triple-negative breast cancer (TNBC) cell lines and TNBC patients, utilizing GEO and TCGA databases. Our current findings have highlighted that the majority of the chosen cell lines, including MDA-MB231 and TNBC patients, exhibit decreased levels of AKT1, PIK3CA, PTEN, and EGFR genes while showing increased levels of KRAS and DNMTs. These observations suggest that these genes are associated with the invasive nature of TNBC.
The impact of lapatinib and BBR on TNBC cells involves genes associated with the PI3K and KRAS pathways. To investigate how lapatinib and BBR influence gene expression under adverse conditions, we conducted two rounds of whole-genome RNA sequencing for both treated and control groups. MDA-MB231 cells were treated separately with 50 μM of lapatinib, BBR, and a combination of 25 μM of each, with PBS-treated groups serving as negative controls (Fig. 5). Our analysis, utilizing KEGG enrichment, revealed that three intracellular pathways (MAPK, PI3K/Akt, KRAS) and cytokine-cytokine receptor genes were most affected.
RNA-seq results of treated MDA-MB231 cells. (Source)
Figure 11 (Source)
Conclusion: A model for cellular defense against lapatinib chemotoxicity in TNBC. Lapatinib results in a dormancy/stem cell-like stage through which oncogenic pathways are reprogrammed by, at first, cell cycle downregulation and then PI3K/Akt pathway upregulation in an EGFR-independent manner. (a) Effects of lapatinib and BBR on genes mainly regulate the cell cycle in MDA-MB231 cells. EGFR and cyclin-dependent kinases CDK6 and nine and Myc- and associated proteins are downregulated in TNBC cells. Instead, MYCN, reported in a few cancers, including neuroblastoma, was upregulated in lapatinib treatment. (b) Effects of lapatinib and BBR on biomarker genes mainly regulate angiogenesis in MDA-MB231 cells. Growth factors such as NGF and PGF and angiogenic biomarkers including ANG, ANGPTL4, RAB11B-AS, and PFKFB3 were upregulated in lapatinib and BBR treatments. (c) Model of resistance to lapatinib in MDA-MB231 cells. T.
Lapatinib targeted 73, 72, and 49 genes in the PI3K/Akt, MAPK, and KRAS pathways, respectively, while BBR targeted 59, 54, and 28 genes (refer to Fig. 5a, b, c). The combination treatment targeted fewer genes than monotherapy. Notably, 30 genes related to the PI3K/Akt pathway were shared between the two monotherapies and combination treatment, whereas 16 genes related to KRAS signaling were shared among all three treatments (Fig. 5c). Differential expression analysis (Fig. 5d–e) identified 26 key genes associated with PI3K/Akt signaling that were upregulated in response to lapatinib and BBR treatment, many of which play roles in tumor progression, cell interactions, and migration (Table 1) (refer to Fig. 5f). This prompted further examination of the function of each upregulated gene in the PI3K/Akt and KRAS pathways, as they might explain the unexpected Akt activation observed in response to lapatinib and BBR, as reported earlier.
Single-cell RNA-seq analysis reveals the distinctive functional composition of immune cells. (Source: 10.1158/2159-8290.CD-20-1500)
New Discovery
c-MET, also known as hepatocyte growth factor receptor (HGFR), is a receptor tyrosine kinase that plays a crucial role in various solid tumors like lung, breast, and liver cancers. Recent single-cell analysis has revealed that c-MET significantly impacts the composition of immune cells within the tumor microenvironment. It promotes an immunosuppressive environment by transforming anti-cancer M1 macrophages into tumorigenic M2 macrophages and converting CD4+Th cells into Treg cells by upregulating PD-L1, TGF-β, and IL-10. Our current research explores the potential of targeting c-MET as an immunotherapeutic strategy.
Traditionally, c-MET was known to have a single ligand, HGF. However, our recent research has discovered new ligands for c-MET in breast cancer. These newly identified ligands can potentially disrupt anticancer immunotherapy efforts by altering the immune cell composition within the tumor microenvironment, ultimately hindering the body's ability to combat cancer effectively. This discovery highlights the need for a deeper understanding of c-MET's role in breast cancer and its implications for immunotherapeutic approaches.
In our future team, we plan to jump much deeper into c-MET mechanism and the functional roles of interactions of c-MET with its novel ligands. The results have yet to be published.