It is reported that primary HER2-specific targeted therapy (tucatinib) resistant or sensitive breast cancers derived from clinical trial patients exhibited differential protein profiles and was proposed as a promising therapeutic strategy for HER2-positive breast cancer.
A novel metabolic-epigenetic mechanism whereby lactate modulates hepatocellular carcinoma sensitivity to targeted therapies through histone lactylation is delineated and suggests AARS1-H4K12la-RAPGEF3 axis may serve as an interventional target to overcome targeted drug resistance, offering a promising strategy to enhance clinical outcomes in HCC patients.
Tanlun Zeng, Wanwan Zhu, Guanqun Sun et al.· Cell Death and Disease· 1 citation
HER2+ breast cancer accounts for 15–20% of invasive breast cancers, and although eight FDA-approved agents, including monoclonal antibodies, tyrosine-kinase inhibitors, and antibody-drug conjugates, have substantially improved patient survival, resistance in the advanced disease setting remains a significant unmet clinical need. Building on our prior preclinical work establishing fibroblasts as drivers of HER2 therapy resistance (Zervantonakis et al., PNAS 2020; Poskus et al., Cell Mol Bioeng 2024), we investigated transcriptional programs driven by cancer-associated fibroblasts (CAF) in patient tumors and patient-derived organoids to uncover new therapeutic targets in HER2+ breast cancer. First, we performed transcriptomic analysis of the NOAH clinical trial dataset and found that SLC39A6 (LIV-1/ZIP6) expression is significantly elevated in patients with residual disease compared to patients with pathologic complete response following HER2-targeted therapy. Importantly, high SLC39A6 expression is also associated with poor patient survival. Using a panel of HER2+ breast cancer cell lines and patient-derived organoids (PDOs), we found that SLC39A6 protein levels were significantly upregulated under CAF co-culture conditions in 4 out of 6 HER2+ breast cancer tumor models but not under monoculture conditions, establishing SLC39A6 as a candidate CAF-induced resistance mediator. To examine the role of SLC39A6 in mediating HER2-therapy resistance, HER2+ PDOs co-cultured with CAFs in 3D matrices were treated with Ladiratuzumab vedotin, an anti-SLC39A6 antibody-drug conjugate (ADC), in combination with lapatinib. The combination induced tumor cell growth suppression in CAF-protected PDOs more effectively than lapatinib, identifying a new strategy to overcome CAF-mediated resistance to HER2-targeted therapy. To dissect CAF-tumor cell interactions with spatial precision, we developed a novel 3D microfluidic co-culture platform that allows patterning of HER2+ PDOs and CAFs in hydrogel matrices and enables real-time, high-resolution imaging to monitor cancer cell growth, death, and CAF-PDO interaction dynamics. The proposed platform recapitulates CAF-rich and CAF-low tumor microenvironments and allows dissection of paracrine vs. contact-dependent CAF signaling by spatially separating CAFs and PDOs in distinct matrix regions. We demonstrated that under homogeneous patterning drug response results mirror those in macroscale 3D co-culture assays, presenting a physiologically relevant platform to study patient-specific CAF-tumor cell interactions and evaluate therapeutic strategies in a controlled 3D microenvironment. These findings identify SLC39A6 as a novel, actionable therapeutic target in CAF-rich HER2+ breast cancer and provide preclinical rationale for SLC39A6-directed ADC combination strategies. Our microfluidic PDO platform establishes a new paradigm for patient-specific drug screening in the context of the stromal tumor microenvironment.
Zeina Habli, Tiangyang Li, Mathew Poskus, Ioannis Zervantonakis. SLC39A6-targeted combination therapy to reverse CAF-induced resistance in HER2+ breast cancer using a microfluidic platform [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A088.
Zeina S. Habli, Tian-Yong Li, Mathew Poskus et al.· Clinical Cancer Research· 0 citations
Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 70% of breast cancer cases. Despite recent advances with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), resistance inevitably develops, often driven by activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. Genetic alterations such as PIK3CA mutations (present in ~ 45% of HR+/HER2- tumors), AKT1 mutations, and PTEN loss contribute to endocrine resistance and poor outcomes. This review summarizes emerging strategies targeting this pathway to overcome resistance in advanced disease. Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3K-mTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population. Next-generation agents, including mutant-selective PI3Kα inhibitors and bi-steric mTOR complex 1 inhibitors, are under active investigation. Optimal sequencing of these agents alongside endocrine therapy and CDK4/6i options remain a critical question, as does integration of genomic testing to guide therapy. Future directions include rational combination strategies, improved biomarker-driven selection, and novel modalities such as proteolysis-targeting chimeras (PROTACs). Collectively, these advances aim to enhance durability of response, minimize toxicity, and improve survival in HR+/HER2- metastatic breast cancer.
L. Lei, M. Canning, E. Sakach et al.· Drugs· 0 citations
BACKGROUND
In non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement, bypass signaling activation commonly leads to resistance against alectinib. Identifying key molecular targets that integrate signals from resistance-driving kinases is crucial for overcoming this resistance. However, these targets have not yet been identified.
METHODS
We generated alectinib-resistant (AR) subclones from H3122 and H2228 cells. Subsequently, we analyzed bypass signaling pathways using western blotting, evaluated drug sensitivity with Cell Counting Kit-8 (CCK-8) assays. To assess the function of Grb2-associated binder 1 (Gab1), we employed siRNA-mediated knockdown and lentiviral shRNA both in vitro and in xenograft models. Additionally, we determined the stability of Gab1 through cycloheximide chase assays.
RESULTS
AR cells demonstrated concurrent activation of the mesenchymal epithelial transition receptor tyrosine kinase (MET) and Rous sarcoma oncogene cellular homolog non-receptor tyrosine kinase (Src), accompanied by upregulation of Gab1. The combined inhibition of MET and Src, as opposed to single-agent blockade, effectively suppressed Gab1/protein kinase B (AKT) signaling and restored sensitivity to alectinib. Gab1 knockdown mirrored the effects of dual kinase inhibition, by disrupting MET/Src/AKT signaling and resensitizing cells to alectinib. Mechanistically, the elevation of Gab1 resulted from post - translational stabilization, with a significantly extended half - life in resistant cells. In vivo, silencing Gab1 inhibited the growth of H3122-AR2 xenografts without causing systemic toxicity, which correlated with decreased phosphorylation of MET, Src and AKT in tumor tissues.
CONCLUSION
In ALK-positive NSCLC with acquired resistance to alectinib, Gab1 emerged as a crucial downstream signaling convergence target of MET and Src co-activation. Targeting this adaptor protein presented a promising therapeutic strategy to overcome bypass-mediated resistance.
Hengyi Chen, Cai-yu Lin, Chen Hu et al.· Cellular Signalling· 0 citations
The study demonstrates that TFEB regulates the expression of the multidrug efflux transporter ATP-binding cassette subfamily G member 2 (ABCG2), a crucial factor in drug resistance mechanisms, and targets TNKS represents a potentially effective therapeutic approach to address cisplatin resistance and improve treatment outcomes in TNBC.
Shariqa Jan, Kaneez Fatima, S. Khan et al.· Molecular Biology Reports· 0 citations
Triple-negative breast cancer (TNBC) remains a clinically challenging subtype characterized by aggressive behavior and limited treatment options. Though docetaxel remains a cornerstone chemotherapy for TNBC, the frequent emergence of resistance highlights the urgent need to identify novel therapeutic targets. In this study, we report that uncoordinated homeobox (UNCX) is upregulated in docetaxel-resistant breast cancer cells, genomically amplified in breast cancer, and associated with poor survival in breast carcinoma patients. Functional studies revealed that UNCX promotes breast cancer cell proliferation, migration and reduces the docetaxel sensitivity. Mechanistically, UNCX functions as a transcriptional repressor by recruiting the SIN3A complex. Genome-wide profiling indicated that the UNCX/SIN3A complex directly binds to the promoters of tumor-suppressor genes including FOXO3, and represses their transcription by removing histone H4K8 crotonylation (H4K8cr). Additionally, the UNCX/SIN3A complex enhances FOXO3 phosphorylation and inhibits its nuclear translocation, further inhibiting its activity. Notably, SIN3A knockdown, FOXO3 overexpression, or crotonylation restoration effectively reverses UNCX-induced malignant phenotypes. These findings collectively establish the UNCX/SIN3A-H4K8cr-FOXO3 axis as a pivotal epigenetic regulator of TNBC progression and chemoresistance, revealing new avenues for targeted therapeutic development against this aggressive breast cancer subtype.
