Comparison of trastuzumab emtansine, trastuzumab deruxtecan, and disitamab vedotin in a multiresistant HER2-positive breast cancer lung metastasis model.

Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.

Extracellular vesicles as modifiers of antibody-drug conjugate efficacy.

Antibody-drug conjugates (ADCs) are a new class of anti-cancer drugs that consist of a monoclonal antibody, a highly potent small-molecule cytotoxic drug, and a chemical linker between the two. ADCs can selectively deliver cytotoxic drugs to cancer cells leading to a reduced systemic exposure and a wider therapeutic window. To date, nine ADCs have received marketing approval, and over 100 are being investigated in nearly 600 clinical trials. The target antigens of at least eight out of the nine approved anti-cancer ADCs and of 69 investigational ADCs are present on extracellular vesicles (EVs) (tiny particles produced by almost all types of cells) that may carry their contents into local and distant cells. Therefore, the EVs have a potential to mediate both the anti-cancer effects and the adverse effects of ADCs. In this overview, we discuss the mechanisms of action of ADCs and the resistance mechanisms to them, the EV-mediated resistance mechanisms to small molecule anti-cancer drugs and anti-cancer monoclonal antibodies, and the EVs as modifiers of ADC efficacy and safety.

Bone marrow microenvironment: The guardian of leukemia stem cells.

Bone marrow microenvironment (BMM) is the main sanctuary of leukemic stem cells (LSCs) and protects these cells against conventional therapies. However, it may open up an opportunity to target LSCs by breaking the close connection between LSCs and the BMM. The elimination of LSCs is of high importance, since they follow cancer stem cell theory as a part of this population. Based on cancer stem cell theory, a cell with stem cell-like features stands at the apex of the hierarchy and produces a heterogeneous population and governs the disease. Secretion of cytokines, chemokines, and extracellular vesicles, whether through autocrine or paracrine mechanisms by activation of downstream signaling pathways in LSCs, favors their persistence and makes the BMM less hospitable for normal stem cells. While all details about the interactions of the BMM and LSCs remain to be elucidated, some clinical trials have been designed to limit these reciprocal interactions to cure leukemia more effectively. In this review, we focus on chronic myeloid leukemia and acute myeloid leukemia LSCs and their milieu in the bone marrow, how to segregate them from the normal compartment, and finally the possible ways to eliminate these cells.

The anticancer effects of pharmacological inhibition of autophagy in acute erythroid leukemia cells.

Although recent studies have reported different aspects of autophagy, from pro-survival to pro-death roles of this process in malignant cells, the underlying mechanisms by which autophagy inhibitors contribute toward the induction of programmed cell death in cancerous cells are still unclear. In the present study, we have attempted to explore some of the molecular features of pharmacological inhibition of autophagy in TF-1 cells (an acute erythroid leukemia model). Our findings indicated that ara-C induces autophagy (with alteration of LC3B, p62, and Beclin-1) in the cells; however, targeting autophagy by 3-methyladenine and chloroquine significantly increased caspase-dependent apoptosis and the sub-G1 compartment in ara-C-treated cells. Moreover, cell cycle analysis showed that 3-MA, as an early-stage autophagy inhibitor, could elevate the cell population in the G0/G1 cell cycle phase, which was associated with upregulation of p21 and p27 expressions. Interestingly, autophagy inhibition was also accompanied by downregulation of c-Myc gene and protein expression levels and upregulated levels of Bax and Bak gene expressions. In addition, following inhibition of autophagy, the levels of tumor-suppressive miRNA (i.e. miR-204) increased, whereas the values of oncogenic miRNAs (including miR-21, miR-221, miR-30a, and miR-17) decreased. Overall, our experiments indicate that autophagy inhibitors (especially chloroquine) seem to be promising agents for combination therapy in acute erythroid leukemia.

Long non-coding RNA PVT1 as a novel candidate for targeted therapy in hematologic malignancies.

Cancerous cells show resistance to various forms of therapy, so applying up to the minute targeted therapy is crucial. For this purpose, long non-coding RNA PVT1 as shown by recent studies is an important oncogene that interacts with vital cellular signaling pathways and different proteins such as c-Myc, NOP2 and LATS2. Due to the enormous role of long non-coding RNAs in development of leukemias, we aimed to show the role of PVT1 knock-down on fate of different hematologic cell lines. owing to this matter, various experiments such as Real-time PCR, cell cycle analysis and apoptosis assay were performed. Meanwhile, proliferation rate by CFSE, protein expression of c-Myc and hTERT by western blot and flow cytometry analysis were investigated. Our results demonstrated that PVT1 knock-down results in c-Myc degradation, proliferation down-regulation, induction of apoptosis and G0/G1 arrest. Simultaneously, for the first time, we posited the relation between this oncogene with hTERT that reduced after PVT1 knock-down. Considering these results, long non-coding RNA PVT1 may be a potential option for targeted therapy in hematologic malignancies.

Long noncoding RNA PVT1: potential oncogene in the development of acute lymphoblastic leukemia.

Emerging evidence shows that long noncoding RNAs (lncRNAs) participate in various cellular processes, and that plasmacytoma variant translocation 1 (PVT1), a newly described oncogene that interacts with various molecules such as p15, p16, NOP2, and c-Myc, is a major contributing factor in tumor development. However, the role of this oncogene remains unknown in the pathogenesis of acute lymphoblastic leukemia (ALL), the most prevalent form of childhood leukemia. In this study, we first measure the expression level of PVT1 in a Jurkat cell line, then small interfering (siRNA) PVT1 is applied to demonstrate the impact of PVT1 knockdown in apoptosis, proliferation, the cell cycle, and its downstream targets. Our findings show that lncRNA was significantly higher in the ALL cell line than normal lymphocytes and that PVT1 knock-down increased the rate of apoptosis, caused G0/G1 arrest in the cell cycle, reduced the proliferation rate, and, above all, reduced the stability of c-Myc protein. All findings were confirmed at the molecular level. Our results may indicate the role of PVT1 knock-down in the suppression of ALL development and might provide an option for targeted therapy for leukemic conditions.