Targeting integrin pathways: mechanisms and advances in therapy

Abstract

Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.

Influence of PD‐L1 expression on the efficacy of EGFR‐TKIs in EGFR‐mutant non‐small cell lung cancer

“…In the current study, the most common concurrent mutation was TP53 . As a well‐known tumor suppressor gene, TP53 mutation has been widely observed in various cancer types, causing the dysfunction of transcription factor p53 and a series of biological function disorders 42 . Previous studies have revealed that EGFRm patients harboring coexisting TP53 mutation had significantly shorter survival time and quicker development of drug resistance than those with TP53w , 43–45 which was verified in our study by showing a 7.6‐months shorter PFS in the TP53m subgroup than the TP53w subgroup.…”

Observation of the protein expression level via naked eye: Pt clusters catalyze non-color molecules into brown-colored molecules in cells

“…Due to the targeting of RGD peptides, peptide-coated Pt clusters can bind with αvβ3 expression in cells ( Guo et al, 2014 ; Yuan et al, 2014 ; Ludwig et al, 2021 ; Pretze et al, 2021 ; Pang et al, 2023 ; Yin et al, 2023 ). Confocal laser scanning microscopy (CLSM) was used to verify the specificity target of Pt in SiHa cells.…”

The kinesin light chain‐2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC

“…P53 is a tumor suppressor gene, which is one of the most common mutation genes in various human tumors. It participates in various activities of cells, such as cell cycle arrest, apoptosis, autophagy, DNA repair, etc 40 . Studies comparing wild‐type and p53 deficient mice show that p53 is necessary for radiation‐induced cell apoptosis, 41 and p53 mutation increases the radioresistance of cancer cells, and partial recovery of p53 function causes radiosensitization 42 .…”