Current Cancer Drug Targets - Volume 22, Issue 4, 2022

The MET protein is a cell surface receptor tyrosine kinase predominately expressed in epithelial cells. Upon binding of its only known ligand, hepatocyte growth factor (HGF), MET homodimerizes, phosphorylates, and stimulates intracellular signalling to drive cell proliferation. Amplification or hyperactivation of MET is frequently observed in various cancer types and it is associated with poor response to conventional and targeted chemotherapy. More recently, emerging evidence also suggests that MET/HGF signalling may play an immunosuppressive role and it could confer resistance to cancer immunotherapy. In this review, we summarized the preclinical and clinical evidence of MET’s role in drug resistance to conventional chemotherapy, targeted therapy, and immunotherapy. Previous clinical trials investigating MET-targeted therapy in unselected or METoverexpressing cancers yielded mostly unfavourable results. More recent clinical studies focusing on MET exon 14 alterations and MET amplification have produced encouraging treatment responses to MET inhibitor therapy. The translational relevance of MET inhibitor therapy to overcome drug resistance in cancer patients is discussed.

Currently, many new treatment strategies are being used for the management of cancer. Among them, chemotherapy based on peptides has been of great interest due to the unique features of peptides. This review discusses the role of peptide and peptides analogues in the treatment of cancer, with special emphasis on their pharmacokinetic modulation and research progress. Low molecular weight, targeted drug delivery, enhanced permeability, etc., of the peptide-linked drug conjugates, lead to an increase in the effectiveness of cancer therapy. Various peptides have recently been developed as drugs and vaccines with an altered pharmacokinetic parameter which has subsequently been assessed in different phases of the clinical study. Peptides have made a great impact in the area of cancer therapy and diagnosis. Targeted chemotherapy and drug delivery techniques using peptides are emerging as excellent tools in minimizing problems with conventional chemotherapy. It can be concluded that new advances in using peptides to treat different types of cancer have been shown by different clinical studies indicating that peptides could be used as an ideal therapeutic method in treating cancer due to the novel advantages of peptides. The development of identifying and synthesizing novel peptides could provide a promising choice to patients with cancer.

Background: Aberrant expression of the MET receptor tyrosine kinase is an oncogenic determinant and a drug target for cancer therapy. Currently, antibody-based biotherapeutics targeting MET are under clinical trials. Objective: Here, we report the preclinical and therapeutic evaluation of a novel anti-MET antibody- drug conjugate PCMC1D3-duocarmycin SA (PCMC1D3-DCM) for targeted cancer therapy. Methods: The monoclonal antibody PCMC1D3 (IgG1a/Κ), generated by a hybridoma technique and specific to one of the MET extracellular domains, was selected based on its high specificity to human MET with a binding affinity of 1.60 nM. PCMC1D3 was conjugated to DCM via a cleavable valine-citrulline dipeptide linker to form an antibody-drug conjugate with a drug-to-antibody ratio of 3.6:1. PCMC1D3-DCM in vitro rapidly induced MET internalization with an internalization efficacy ranging from 6.5 to 17.2h dependent on individual cell lines. Results: Studies using different types of cancer cell lines showed that PCMC1D3-DCM disrupted the cell cycle, reduced cell viability, and caused massive cell death within 96h after treatment initiation. The calculated IC50 values for cell viability reduction were 1.5 to 15.3 nM. Results from mouse xenograft tumor models demonstrated that PCMC1D3-DCM in a single dose injection at 10 mg/kg body weight effectively delayed xenograft tumor growth up to two weeks without signs of tumor regrowth. The calculated tumoristatic concentration, a minimal dose required to balance tumor growth and inhibition, was around 2 mg/kg body weight. Taken together, PCMC1D3-DCM was effective in targeting the inhibition of tumor growth in xenograft models. Conclusion: This work provides the basis for the development of humanized PCMC1D3-DCM for MET-targeted cancer therapy in the future.

Objective: Cutaneous T cell lymphoma (CTCL) is a kind of extranodal non-Hodgkin Tcell lymphoma without healable treatment in the clinic. JAK2 amplification in CTCL patients makes it a potential target for CTCL treatment. In the present study, we aimed to evaluate the anticancer effect of ND-16, a novel nilotinib derivate, on CTCL cells and the underlying mechanism targeting JAK2. Methods and Results: We found that ND-16 was capable of regulating JAK2 and had a selective inhibitory effect on CTCL H9 cells. The surface plasmon resonance and molecular docking study indicated ND-16 bound to JAK2 with a high binding affinity. Further investigation revealed that ND-16 inhibited the downstream cascades of JAK2, including STATs, PI3K/AKT/mTOR, and MAPK pathways, followed by regulation of Bcl-2 family members and cell cycle proteins CDK/- Cyclins. Flow cytometry analysis confirmed these results that ND-16-treated H9 cells showed cell apoptosis and cell cycle arrest at S-phase. Conclusion: ND-16 may be of value in a potential therapy for the management of CTCL.

Background: Lung adenocarcinoma (LUAD), the most common type of lung cancer associated with poor prognosis, has become a major health problem. IGF2BPs are types of N⁶-methyladenosine reader proteins, comprising IGF2BP1, IGF2BP2, and IGF2BP3, that promote LUAD progression. However, the expression profiles and prognostic value of IGF2BPs in LUAD remain unclear. Objective: This study aimed to analyze the expression profiles and prognostic significance of the IGF2BP family in lung adenocarcinoma. Methods: In this study, we included tissue data of LUAD patients and normal or para-carcinoma from the TCGA database and the GTEx project. Using survival analysis, Kaplan-Meier curves, and Cox proportional hazards model, we analyzed the expression profiles and prognostic significance of the IGF2BP family. Results: Patients with high expression levels of IGF2BPs showed a significant association with poor overall survival (p < 0.05). Moreover, the somatic mutation rates of IGF2BP1, IGF2BP2, and IGF2BP3 were determined as 2.65, 1.59, and 1.76%, respectively, by investigating the genetic mutation. In addition, there were significant associations between TMB and IGF2BP family expression profiles, which positively correlated with the expression of PD-1 (p < 0.05). Cox proportional hazard model for LUAD showed the risk score for IGF2BP1, p-TNM stage, and so forth, all independent prognostic indicators for LUAD patients. Finally, the co-expression genes were obtained to build a PPI network and analyze the hub genes of the IGF2BP family. Conclusion: Our study provides further insights into the role of the IGF2BP family in LUAD and identifies 10 genes that may be associated with IGF2BPs in LUAD patients.