PSMA-encoding FOLH1 gene expression correlates with neoangiogenesis and predicts PFS in m-ccRCC patients treated with sunitinib TKI, suggesting that PSMA PET could be explored as a noninvasive biomarker for guiding CST choice (IO/IO or IO/VEGFi) as well as prediction of treatment response to VEGFi in m-ccRCC patients.

BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

We use cryo-electron microscopy and biophysical methods to determine the structural basis of ligand binding and pH-dependent dimerization of Sev, and we discuss the implications in the process of Sev activation. The Sev human homolog, receptor oncogene from sarcoma 1 (ROS1), is associated with oncogenic transformations, and we discuss their structural similarities.

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ctDNA-based analysis facilitates assessment of disease status and genomic profiles, thus potentially assisting in identifying optimal therapeutic strategies for advanced GIST patients.

No abstract available

In this particular case, treatment with crizotinib demonstrated some initial efficacy, which suggests that this might be a promising strategy for patients with advanced MPM with an ALK gene mutation. This required further research and evaluation in the future.

In addition, there are various regions in each protein that are predicted to have greater conformational fluctuations as compared to others, which may represent attractive areas to target to halt the progression of the interaction. These insights deepen our understanding of the PROS1-MERTK interaction role in immune modulation and tumor progression, unveiling potential targets for cancer immunotherapy.

P3, N=400, Not yet recruiting, EyePoint Pharmaceuticals, Inc.

The tumor growth inhibitory rate was 99.36% for dabrafenib, trametinib, and osimertinib; 99.25% for osimertinib plus vemurafenib; 98.92% for osimertinib, encorafenib, and cetuximab; and 62.83% for pemetrexed plus carboplatin. NGS analysis identified major resistance mechanisms following the triple-targeted therapy, including the EGFR-dependent pathway, EGFR and BRAF V600E-dependent pathway, and an off-target mechanism. EGFR/BRAF/MEK triple-targeted therapy is an effective and safe approach for treating EGFR-mutated NSCLC patients resistant to EGFR-TKIs with acquired BRAF V600E mutations.

TKI achieved durable disease control in epidermal growth factor receptor mutation positive NSCLC patients with CM, while improving visual function. TKI can be considered as an alternative to conventional orbital radiotherapy or chemotherapy for these patients in view of the rapid visual recovery.

Early SBRT for primary lung tumors may overcome targeted resistance in advanced EGFRm NSCLC patients combined with EGFR-TKIs without serious toxicities, especially for EGFR exon 19-del. ChiCTR-OIN-17013920.

P=N/A, N=39, Recruiting, Jinling Hospital, China

Gefitinib treatment affected NSCLC resistant cells...Both INHBA silencing and X-ray treatment inhibited EMT development. This study demonstrated that INHBA silencing ameliorates EGFR-TKI resistance and enhances the therapeutic effect of radiotherapy in NSCLC.

The utility of the platelet-lymphocyte ratio (PLR) in patients treated with osimertinib is undetermined...Third generation EGFR TKIs may be more efficacious in treating patients with laboratory findings previously shown to predict poor survival. The significant changes in peripheral cell counts suggest variability tumor microenvironment changes dependent on the generation of TKI received.

P3, N=400, Recruiting, EyePoint Pharmaceuticals, Inc.

Pregnancy by TFR or treatment with IFN-α could be a safe and feasible way for patients with CML. However, a substantial duration of treatment with a TKI before conception may be needed for planned pregnancy. Planning and evaluation for pregnancy should be considered at the time of CML onset for female patients with childbearing potential.

ARHGAP12 expression is elevated in HCC and TKI-resistant HCC, and its regulatory role in FA may underlie the TKI-resistant phenotype.

We verify the structure using mutagenesis and confirm that the conformation corresponds to the active state of the receptor. Subsequent study of TrkB interaction with the antidepressant drug fluoxetine, and the antipsychotic drug chlorpromazine, provides a clear self-consistent model, describing the mechanism by which fluoxetine activates the receptor by binding to its transmembrane domain.

P2, N=29, Recruiting, Northwestern University | Not yet recruiting --> Recruiting

In this review, we provide an exhaustive overview of the diverse approaches that use PTK7 as a new molecular target for cancer therapy in different tumor types. We discuss current therapies and future strategies including chimeric antigen receptor-T cells, antibody-drug conjugates, aptamers, based on up-to-date literature and ongoing research progress.

In summary, the dual inhibition of GPX4 and BCR-ABL presents a promising therapeutic strategy to synergistically target blast cells and drug-insensitive LSCs in patients, offering potential avenues for advancing leukemia treatment.

Conclusion Axl receptor was not associated with all of the clinicopathological variables, the expression values were high in malignant tumors in comparison with the benign tumors, and it was found that Axl receptor expression was associated with low/intermediate grade, which is considered a favorable prognostic factor. Although Axl receptor expression was previously linked with proliferation and invasiveness in BC, its association with the Ki-67 proliferation marker and BCL-2 anti-apoptotic protein was not observed.

ARAF amplification was identified in 5-8% of EGFR-TKI-resistant tumors. The possible roles of ARAF in SCLC transformation warrant further investigation.

A statistical analysis was performed to assess the overall survival status. Our data suggest an important role of KIT in the etiopathogenesis of canine MCTs and indicate that the anomalous cytoplasmatic distribution of KIT is potentially related to a lower efficacy of tyrosine kinase inhibitors, thus providing a significant prognostic information about the treatment outcome.

Anticancer efficacy of PPL, erlotinib (ERL), gefitinib (GEF), and cisplatin (CIS) were investigated in H1299 and H1975 cell lines. Treatment with PPL alone and in combination induced anti-mitogenic and apoptotic responses at the molecular level. PPL sensitized lung cancer cells to EGFR-TKI and induced potent cytotoxic effects at low concentrations.

In animal studies, co-injection of cancer cells with PCs compromises TKI effectiveness, independently of blood vessel functions, while inhibition of β5-integrin restores tumor cell sensitivity. Overall, the findings highlight direct crosstalk between cancer cells and pericytes, impacting TKI sensitivity via IL32-β5-integrin paracrine signaling, proposing an enhanced therapeutic approach for EGFR-mutated patients.

Additionally, there was a significant correlation between the movement of the β3-αC loop and the P-loop, which controls the dimensions of the adenine-binding cavity of the C-spine region. Overall, understanding these significant motions of the Syk kinase domain enhances our knowledge of its functional regulatory mechanism and can guide future research.

Combined with other agents, some regimens have shown improved benefits in overcoming drug resistance and prolonging patient survival. It is imperative to focus on developing novel EGFR-TKIs and investigate innovative combination therapies to maximize patient benefit.

After the initial treatment with ensartinib, the patient experienced intracranial disease progression...Subsequent thoracic RT resulted in a partial response of the primary tumor; however, new brain and bone metastases were detected, prompting a switch to lorlatinib...Despite pembrolizumab treatment, the patient's condition deteriorated, and she passed away...Our findings revealed heterogeneity in ALK mutations and responses to ALK-TKIs, necessitating the close monitoring of genetic subtypes and associated mutations for tailored treatment strategies. Maintaining a heightened awareness of potential intestinal metastasis and vigilance in monitoring intestinal symptoms and abdominal metastases are pivotal for managing advanced lung adenocarcinoma.

A 43-year-old, female diagnosed with T4N3M1c NSCLC harboring the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion variant 1 (EML4-ALK v.1) and TP53 co-mutation, displayed only mixed response after three months and highly symptomatic progression after 6 months of first-line brigatinib treatment. The latter may represent a mechanism of intrinsic ALK-TKI resistance and its recognition by FISH, in NGS-negative cases, may be considered before initiating first-line treatment. This recognition is clinically important as combined therapy with ALK-TKI and MET-inhibitor should be the preferred first-line treatment.

Two compounds, namely, radotinib and capmatinib, were identified as top compounds using molecular docking. The Western blot analysis assay showed that the phosphorylation level of STAT3 was significantly decreased upon radotinib treatment. Taken together, our findings suggest that radotinib, which is currently used in the treatment of chronic myeloid leukemia (CML), could be considered as a potential candidate for repurposing in the treatment of HCC.

First-line MWA significantly improved the outcomes of patients with untreated EGFR-mutant advanced LUAD treated with TKIs. Complete ablation predicts a better prognosis.

No abstract available

In LCBM syngeneic murine models with TKI-sensitive or TKI-resistant EGFR mutations, combining CTLA4 blockade with TKIs demonstrates enhanced efficacy over TKI monotherapy or TKIs with PD1 blockade. These findings provide insights into the TKI resistance mechanisms and highlight the potential of CTLA4 blockade in effectively overcoming TKI resistance in LCBM.

Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT.

Mechanistically, the present results indicated that RON may affect ferroptosis, glycolysis and chemotherapy sensitivity by regulating MAPK/cAMP‑response element binding protein (CREB) signaling in thyroid cancer cells. In conclusion, the present study demonstrated that RON affected ferroptosis, glycolysis and chemotherapy sensitivity in thyroid cancer cells by regulating MAPK/CREB signaling, demonstrating its potential as a therapeutic target in thyroid cancer cells.

The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications.

P1/2, N=133, Recruiting, Beijing Konruns Pharmaceutical Co., Ltd. | Trial completion date: Apr 2025 --> Dec 2025 | Trial primary completion date: Apr 2024 --> Oct 2025

P1, N=207, Recruiting, Beijing Konruns Pharmaceutical Co., Ltd. | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Jul 2023 --> Oct 2025

Low PYK2 expression was found in tumor tissues, especially metastases, and significantly correlated with patient prognosis. Moreover, decreased PYK2 induces EMT by activating Wnt/β-catenin signaling, which is the potential mechanism of CRC metastasis. Regulating the expression of PYK2 to suppress tumor cell metastasis may represent a promising therapeutic strategy for metastatic CRC.