Bruton’s tyrosine kinase (BTK) inhibitor is a promising novel agent that has potential efficiency in B-cell malignancies. It took approximately 20 years from target discovery to new drug approval. The first-in-class drug ibrutinib creates possibilities for an era of chemotherapy-free management of B-cell malignancies, and it is so popular that gross sales have rapidly grown to more than 230 billion dollars in just 6 years, with annual sales exceeding 80 billion dollars; it also became one of the five top-selling medicines in the world. Numerous clinical trials of BTK inhibitors in cancers were initiated in the last decade, and ~73 trials were intensively announced or updated with extended follow-up data in the most recent 3 years. In this review, we summarized the significant milestones in the preclinical discovery and clinical development of BTK inhibitors to better understand the clinical and commercial potential as well as the directions being taken. Furthermore, it also contributes impactful lessons regarding the discovery and development of other novel therapies.

With the development of radiotherapeutic oncology, computer technology and medical imaging technology, radiation therapy has made great progress. Research on the impact and the specific mechanism of radiation on tumors has become a central topic in cancer therapy. According to the traditional view, radiation can directly affect the structure of the DNA double helix, which in turn activates DNA damage sensors to induce apoptosis, necrosis, and aging or affects normal mitosis events and ultimately rewires various biological characteristics of neoplasm cells. In addition, irradiation damages subcellular structures, such as the cytoplasmic membrane, endoplasmic reticulum, ribosome, mitochondria, and lysosome of cancer cells to regulate various biological activities of tumor cells. Recent studies have shown that radiation can also change the tumor cell phenotype, immunogenicity and microenvironment, thereby globally altering the biological behavior of cancer cells. In this review, we focus on the effects of therapeutic radiation on the biological features of tumor cells to provide a theoretical basis for combinational therapy and inaugurate a new era in oncology.

The extracellular matrix (ECM) serves as signals that regulate specific cell states in tumor tissues. Increasing evidence suggests that extracellular biomechanical force signals are critical in tumor progression. In this study, we aimed to explore the influence of ECM-derived biomechanical force on breast cancer cell status. Experiments were conducted using 3D collagen, fibrinogen, and Matrigel matrices to investigate the role of mechanical force in tumor development. Integrin-cytoskeleton-AIRE and DDR-STAT signals were examined using RNA sequencing and western blotting. Data from 1358 patients and 86 clinical specimens were used for ECM signature-prognosis analysis. Our findings revealed that ECM-derived mechanical force regulated tumor stemness and cell quiescence in breast cancer cells. A mechanical force of ~45 Pa derived from the extracellular substrate activated integrin β1/3 receptors, stimulating stem cell signaling pathways through the cytoskeleton/AIRE axis and promoting tumorigenic potential and stem-like phenotypes. However, excessive mechanical force (450 Pa) could drive stem-like cancer cells into a quiescent state, with the removal of mechanical forces leading to vigorous proliferation in quiescent cancer stem cells. Mechanical force facilitated cell cycle arrest to induce quiescence, dependent on DDR2/STAT1/P27 signaling. Therefore, ECM-derived mechanical force governs breast cancer cell status and proliferative characteristics through stiffness alterations. We further established an ECM signature based on the fibrinogen/fibronectin/vitronectin/elastin axis, which efficiently predicts patient prognosis in breast cancer. Our findings highlight the vital role of ECM-derived mechanical force in governing breast cancer cell stemness/quiescence transition and suggest the novel use of ECM signature in predicting the clinical prognosis of breast cancer.

Reprogramming of cellular metabolism is a hallmark of cancer. Mitochondrial ATP synthase (MAS) produces most of the ATP that drives the cell. High expression of the MAS-composing proteins is found during cancer and is linked to a poor prognosis in glioblastoma, ovarian cancer, prostate cancer, breast cancer, and clear cell renal cell carcinoma. Cell surface-expressed ATP synthase, translocated from mitochondrion to cell membrane, involves the angiogenesis, tumorigenesis, and metastasis of cancer. ATP synthase has therefore been considered a therapeutic target. We review recent various ATP synthase inhibitors that suppress tumor growth and are being tested for the clinic.