Accurately predicting the binding affinity between proteins and ligands is crucial in drug screening and optimization, but it is still a challenge in computer-aided drug design. The recent success of AlphaFold2 in predicting protein structures has brought new hope for deep learning (DL) models to accurately predict protein-ligand binding affinity. However, the current DL models still face limitations due to the low-quality database, inaccurate input representation and inappropriate model architecture. In this work, we review the computational methods, specifically DL-based models, used to predict protein-ligand binding affinity. We start with a brief introduction to protein-ligand binding affinity and the traditional computational methods used to calculate them. We then introduce the basic principles of DL models for predicting protein-ligand binding affinity. Next, we review the commonly used databases, input representations and DL models in this field. Finally, we discuss the potential challenges and future work in accurately predicting protein-ligand binding affinity via DL models.

Prediction of protein-ligand binding affinity via deep learning models.

PURPOSE
DYNLT3 is identified as an age-related gene. Nevertheless, the specific mechanism of its carcinogenesis in breast tumor has not been clarified. This research aims to elucidate the role and the underlying molecular pathways of DYNLT3 on breast cancer tumorigenesis.


METHODS
The differential expression of DYNLT3 among breast cancer, breast fibroids, and normal tissues, as well as in various breast cancer cell lines were detected by immunohistochemical staining, real-time quantitative reverse transcription-PCR and Western blotting, respectively. Additionally, the role of DYNLT3 on cell viability and proliferation were observed through cell counting kit-8, bromodeoxyuridine, and colony formation experiments. Migratory and invasive abilities was envaulted by wound healing and Transwell methods. Apoptotic cells rate was examined by flow cytometry. Furthermore, nude mice xenograft models were established to confirm the role of DYNLT3 in tumor formation in vivo.


RESULTS
DYNLT3 expression was highly rising in both breast cancer tissues and cells. DYNLT3 knockdown obviously suppressed cell growth, migration and invasion, and induced cell apoptosis in MDA-MB-231 and MCF-7 breast cancer cells. The overexpression of DYNLT3 exerted the opposite effect in MDA-MB-231 cells. Moreover, DYNLT3 knockdown inhibited tumor formation in vivo. Mechanistically, an elevation of N-cadherin and vimentin levels and a decline of E-cadherin were observed when DYNLT3 was upregulated, which was reversed when DYNLT3 knockdown was performed.


CONCLUSION
DYNLT3 may function as a tumor-promotor of age-associated breast cancer, which is expected to provide experimental basis for new treatment options.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cam4.6173

The role of DYNLT3 in breast cancer proliferation, migration, and invasion via epithelial-to-mesenchymal transition.

INTRODUCTION
Targeted therapy is used to treat lung adenocarcinoma caused by epidermal growth factor receptor (EGFR) mutations in the tyrosine kinase domain and rare subtypes (<5%) of non-small cell lung cancer. These subtypes include fusion oncoproteins like anaplastic lymphoma kinase (ALK), ROS1, rearranged during transfection (RET), and other receptor tyrosine kinases (RTKs). The use of diverse selective oral inhibitors, including those targeting rat sarcoma viral oncogene homolog (KRAS) mutations, has significantly improved clinical responses, extending progression-free and overall survival.


AREAS COVERED
Resistance remains a critical issue in lung adenocarcinoma, notably in EGFR mutant, echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion, and KRAS mutant tumors, often associated with epithelial-to-mesenchymal transition (EMT).


EXPERT OPINION
Despite advancements in next generation EGFR inhibitors and EML4-ALK therapies with enhanced brain penetrance and identifying resistance mutations, overcoming resistance has not been abated. Various strategies are being explored to overcome this issue to achieve prolonged cancer remission and delay resistance. Targeting yes-associated protein (YAP) and the mechanisms associated with YAP activation through Hippo-dependent or independent pathways, is desirable. Additionally, the exploration of liquid-liquid phase separation in fusion oncoproteins forming condensates in the cytoplasm for oncogenic signaling is a promising field for the development of new treatments.

Deterministic reprogramming and signaling activation following targeted therapy in non-small cell lung cancer driven by mutations or oncogenic fusions.

ABSTRACT Background Breast cancer is a multifactorial disease that affects many women worldwide. Age is the most important risk factor for breast cancer, with an increased incidence markedly after the age of 50. The relationships of aging to breast cancer have been thoroughly examined, and notable connections regarding various age‐related changes in breast tissue, as well as age‐related hormonal changes, have been defined, increasing the risk of breast cancer. In order to create opportunities for early detection and prevention, it is vital that we understand the risk factors of breast cancer, including hypertension and physical activity, to name only a few factors. Methods This review examines breast cancer incidence and rate, associations of aging and breast cancer, and the significance of better understanding this connection. The review will consider how aging interacts with breast cancer risk and will review breast cancer biology, examination of breast tissue, hormone changes with age, and other age‐related factors that may influence breast cancer risk and/or development. We will also explore breast cancer risk factors, including genetic constitution and lifestyle factors, and how these factors all interact with age characteristics. In addition, we will review strategies to reduce the risk of breast cancer and briefly review breast cancer screening guidelines, not limited to but including some of the difficulties of appropriate screening for an older woman. Results In summary, this review serves to underscore the awareness and understanding of breast cancer in connection with aging, and by acknowledging risk factors, flattening the curve of acceptance, and encouraging early detection and intervention through appropriate screening, we may alleviate the burden of breast cancer in older women. 

Breast Cancer and Aging: Understanding the Complex Relationship and Implications for Prevention and Screening

Abstract In patients with non‐small cell lung cancer (NSCLC), oncogenic variants present in &lt;5% of cases are considered rare, the predominant of which include human epidermal growth factor receptor 2 ( HER2 ) mutations, mesenchymal–epithelial transition ( MET ) alterations, c‐ros oncogene 1 ( ROS1 ) rearrangements, rearrangement during transfection ( RET ) fusions, v‐raf mouse sarcoma virus oncogene homolog B1 ( BRAF ) mutations, and neurotrophic troponin receptor kinase ( NTRK ) fusions. Brain metastases (BMs) occur in approximately 10%–50% of patients with NSCLC harboring rare genetic variants. The recent advent of small‐molecule tyrosine kinase inhibitors and macromolecular antibody–drug conjugates (ADCs) has conferred marked survival benefits to patients with NSCLC harboring rare driver alterations. Despite effective brain lesion control for most targeted agents and promising reports of intracranial remission associated with novel ADCs, BM continues to be a major therapeutic challenge. This review discusses the recent advances in the treatment of NSCLC with rare genetic variants and BM, with a particular focus on intracranial efficacy, and explores future perspectives on how best to treat these patients. 

Spotlight on the treatment of non‐small cell lung cancer with rare genetic alterations and brain metastasis: Current status and future perspectives

Abstract RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RET L730 , RET V804 and RET G810 ), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers. 

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations

Author Correction: Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

Simple Summary The incidence of breast cancer has increased rapidly in recent years. Aging is one of the risk factors for advanced breast cancer. More and more studies have been conducted on the influence of the aging microenvironment on breast cancer. In this review, we summarize the effects of physical changes in the aging microenvironment, senescence-associated secretory phenotypes, and senescent stromal cells on the initiation and progression of breast cancer and the underlying mechanisms. In addition, we also discuss potential targets for senotherapeutics and senescence-inducing agents in the aging microenvironment of breast cancer. We hope this review can provide some directions for future research on the aging microenvironment in breast cancer. Abstract Aging is one of the risk factors for advanced breast cancer. With the increasing trend toward population aging, it is important to study the effects of aging on breast cancer in depth. Cellular senescence and changes in the aging microenvironment in vivo are the basis for body aging and death. In this review, we focus on the influence of the aging microenvironment on breast cancer. Increased breast extracellular matrix stiffness in the aging breast extracellular matrix can promote the invasion of breast cancer cells. The role of senescence-associated secretory phenotypes (SASPs) such as interleukin-6 (IL-6), IL-8, and matrix metalloproteases (MMPs), in breast cancer cell proliferation, invasion, and metastasis is worthy of exploration. Furthermore, the impact of senescent fibroblasts, adipocytes, and endothelial cells on the mammary matrix is discussed in detail. We also list potential targets for senotherapeutics and senescence-inducing agents in the aging microenvironment of breast cancer. In conclusion, this review offers an overview of the influence of the aging microenvironment on breast cancer initiation and progression, with the aim of providing some directions for future research on the aging microenvironment in breast cancer.

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Recent Advances in the Aging Microenvironment of Breast Cancer

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Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations

Author Correction: Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

Recent Advances in the Aging Microenvironment of Breast Cancer