Cellular Biology Research

Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With the widespread use of the drug, we must deeply analyze the dilemma of the agents and seek a breakthrough in the treatment prospect. Over the past decades, these agents have demonstrated dramatic efficacy, especially in patients with melanoma and non-small cell lung cancer (NSCLC). Nonetheless, in the field of a broad concept of solid tumours, non-specific indications, inseparable immune response and side effects, unconfirmed progressive disease, and complex regulatory networks of immune resistance are four barriers that limit its widespread application. Fortunately, the successful clinical trials of novel ICB agents and combination therapies, the advent of the era of oncolytic virus gene editing, and the breakthrough of the technical barriers of mRNA vaccines and nano-delivery systems have made remarkable breakthroughs currently. In this review, we enumerate the mechanisms of each immune checkpoint targets, associations between ICB with tumour mutation burden, key immune regulatory or resistance signalling pathways, the specific clinical evidence of the efficacy of classical targets and new targets among different tumour types and put forward dialectical thoughts on drug safety. Finally, we discuss the importance of accurate triage of ICB based on recent advances in predictive biomarkers and diagnostic testing techniques. https://lnkd.in/ejimpwy6

KRAS-mutant non-small cell lung cancers (NSCLC) with co-occurring STK11/LKB1 and KEAP1 mutations represent an aggressive subset with poor outcomes and resistance to standard immunotherapy and chemotherapy. These patients urgently need new treatment options. Methods: Researchers screened 20 NSCLC cell lines for sensitivity to ATR inhibitors, validated findings in isogenic cell line models, and tested combinations with chemotherapy and immunotherapy in preclinical models. Clinical validation came from the HUDSON trial analyzing patients treated with ceralasertib plus durvalumab. Key findings include: - Cell lines with STK11/LKB1 and/or KEAP1 mutations showed enhanced sensitivity to ATR inhibitors - LKB1 loss increased replication stress, while KEAP1 mutations activated compensatory ATR-CHK1 signaling - ATR inhibition synergized with gemcitabine and reversed immunosuppressive tumor phenotypes - In the HUDSON trial, patients with STK11/KEAP1 alterations had significantly longer progression-free survival with ceralasertib plus durvalumab (6.0 vs 2.6 months, p=0.008) Conclusions: This work suggests that STK11/LKB1 and KEAP1 alterations could serve as biomarkers for selecting patients who would benefit from ATR inhibitor-based combination therapies. A phase III trial (LATIFY) is currently testing this approach in NSCLC patients who have progressed on immunotherapy and chemotherapy. Paper and research by Ana Galan-Cobo and larger team

Currently in Phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer (NSCLC), BBO-8520 is a first-in-class, direct dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C forms providing optimal target coverage of the active protein and potentially could overcome the adaptive resistance to the known KRASG12C (OFF)-only inhibitors observed in association with increased expression and activity of KRASG12C(ON). BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine and disables effector binding to KRASG12C(ON) and exhibits potent signaling inhibition in growth factor activated states where current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. https://lnkd.in/g8FjCG2a

Excited to share our latest work on selective autophagy inhibition in cancer: "Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer" Published in EMBO Molecular Medicine https://lnkd.in/eFEpSE5E a collaborative work from Ana Maria Cuervo and Evris Gavathiotis labs Chaperone-mediated autophagy (CMA) is often upregulated in cancers, supporting tumor growth and therapy resistance — yet it has remained undruggable. In this study, we identify NCoR1/RARα interaction as a druggable mechanism and report the first-in-class, selective CMA inhibitor that lead to reduced tumor growth: Key Highlights: -RARα/NCoR1 interaction transcriptionally regulates CMA in NSCLC -CIM7, a novel small molecule, disrupts this complex -CIM7 selectively inhibits CMA (not macroautophagy) -Preferential activity in cancer cells with no observed toxicity -Demonstrates in vivo tumor growth inhibition in NSCLC models This work provides a new pharmacologic strategy to target CMA without broadly impairing lysosomal function — a major step forward for autophagy-based cancer therapies and other conditions driven by abnormal upregulation of CMA. Huge congratulations to Mericka McCabe, PhD for leading this study and to the whole team! Albert Einstein College of Medicine, Montefiore Health System Montefiore Einstein Comprehensive Cancer Center #CancerResearch #Autophagy #CMA #NSCLC #DrugDiscovery #RARalpha #PrecisionMedicine #MolecularMedicine #TargetedTherapy #EMBO

🚨 FDA Accelerated Approval: Zongertinib (Hernexeos) 🚨 A new targeted therapy option for a rare molecular subset of lung cancer has just entered our clinic shelves. On August 8, 2025, the US FDA granted accelerated approval to zongertinib (Hernexeos, Boehringer Ingelheim) for adults with unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) harboring HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, after prior systemic therapy, as detected by an FDA-approved test. The Oncomine Dx Target Test was simultaneously approved as the companion diagnostic. 🔬 Why this matters HER2-mutant NSCLC is uncommon (~2–4% of non-squamous cases) but biologically aggressive, with limited options beyond chemotherapy or antibody–drug conjugates (ADCs). Until now, trastuzumab deruxtecan (T-DXd) was the only FDA-approved HER2-targeted agent in this setting. Zongertinib now offers: Oral administration (once daily) High response rates Activity even after prior HER2-ADC exposure 💊 Dosing <90 kg: 120 mg PO once daily ≥90 kg: 180 mg PO once daily With or without food; continue until progression or unacceptable toxicity. 📊 Efficacy (Beamion LUNG-1) BICR-assessed, RECIST v1.1, in patients with HER2-mutant NSCLC who had progressed after platinum chemo ± immunotherapy: No prior HER2-ADC (n=71): ORR 75% (95% CI: 63–83) 58% had duration of response ≥6 months Prior HER2-ADC (n=34): ORR 44% (95% CI: 29–61) 27% had duration of response ≥6 months Early presentations suggest intracranial activity in patients with brain metastases, an important consideration in NSCLC care. ⚠️ Key safety points Hepatotoxicity (monitor LFTs regularly) Left ventricular dysfunction (baseline and periodic cardiac evaluation) Interstitial lung disease/pneumonitis (prompt evaluation of new respiratory symptoms) Embryo-fetal toxicity (effective contraception required) 🔄 How I see it fitting in For eligible patients, zongertinib offers a convenient oral option with impressive activity both before and after ADC therapy. In ADC-naïve patients: potential to achieve high ORR without infusion-related logistics. Post-T-DXd: valuable salvage option with meaningful responses. Choice between T-DXd and zongertinib first may depend on ILD risk, cardiac profile, CNS disease, patient preference, and drug accessibility. 📌 Take-home The arrival of zongertinib signals the rapid evolution of precision medicine in lung cancer—where HER2 mutation is no longer a biologic orphan. As confirmatory trials read out, we’ll learn whether its benefits extend into earlier lines of therapy and how best to sequence it with ADCs. #Oncology #LungCancer #NSCLC #HER2 #PrecisionMedicine #FDAApproval #MedicalOncology #TargetedTherapy

🚨 Excited to share our latest in Experimental Hematology & Oncology: “Advancing precision antibody–drug conjugate therapy: unique proteogenomic profiles of tumor subsets in NSCLC” 🔗 https://bit.ly/3IoYHK4 In an era of #ADCs reshaping thoracic oncology, biomarker-driven patient selection is critical. In this study, we performed integrated transcriptomic and proteomic profiling across NSCLC samples and identified four distinct, mutually exclusive subtypes defined by: ◼️ CEACAM5 ◼️ MET ◼️ TACSTD2 (Trop2) ◼️ FOLR1 📌 Key insights: 1. High RNA–protein correlation for these targets, an important finding in era of #RNA NGS 2. Defined targetable subgroups independent of histology or mutation status 3. Framework for biomarker-first ADC development in lung cancer Proud of this collaboration and excited for the future of precision ADC therapy in NSCLC. Vivek Subbiah, MD Rajat Thawani #Oncology #ADC #NSCLC OncoAlert UAB O'Neal Comprehensive Cancer Center International Association for the Study of Lung Cancer

The paradigm of KRAS as an "undruggable" target has been replaced by a sophisticated landscape of allele-specific and state-specific inhibition. A recent review in Cancer Cell (Riedl et al., 2026) synthesizes the current transition from first-generation G12C inhibitors to the next frontier of precision oncology. Key Scientific & Clinical Developments: • Targeting the Active State: Move beyond GDP-bound ("OFF") state inhibitors to GTP-bound ("ON") state inhibitors, expanding the therapeutic window for non-covalent targeting. • Allele Diversity: Evolution from G12C cysteine-tagging to selective inhibitors for G12D and G12V, and the emergence of "Pan-KRAS" inhibitors targeting the conserved switch II pocket. • Mechanisms of Escape: Addressing "bypass signaling" and vertical reactivation of the MAPK pathway through rational combinations (e.g., SHP2, SOS1, or EGFR inhibition). • Clinical Expansion: Translating success in NSCLC to high-unmet-need populations in Pancreatic (PDAC) and Colorectal Cancer (CRC) through improved bioavailability and combinatorial synergy. As we move toward KRAS degraders (PROTACs) and immunomodulatory combinations, the focus shifts from achieving initial response to overcoming adaptive resistance. Full Study: https://lnkd.in/gZGGXk5i #MolecularOncology #KRAS #DrugDiscovery #PrecisionMedicine #CancerResearch #SignalTransduction

Dr Luis E. Raez - #MemorialCancerInstitute, #MemorialHealthcareSystem, Miami, USA Dr. Luis Raez reviews three key genetic fusions in non-small cell lung cancer (NSCLC): NTRK, RET, and NRG1. He begins with NTRK fusions, rare but highly actionable mutations found across multiple tumor types, highlighting the remarkable responses seen with TRK inhibitors like larotrectinib and entrectinib. Next, he discusses RET rearrangements, found in about 1–2% of lung adenocarcinomas, emphasizing the effectiveness of selective RET inhibitors such as selpercatinib and pralsetinib. Finally, Dr. Raez addresses NRG1 fusions, an emerging and less understood aberration, often seen in invasive mucinous adenocarcinomas, where HER3-targeted therapies are showing early promise in clinical trials. Dr. Raez underscores the importance of comprehensive molecular profiling to detect these fusions and offer patients personalized and effective treatment options. #lungcancer #lcsm

Hi friends, it's #LungCancer Wednesday! Here's what happened last week: R 1️⃣ OS1 Fusion Variants and TKI Efficacy in NSCLC New research underscores the importance of breakpoint mapping in ROS1-positive NSCLC. Patients with breakpoints in introns 33/34 and canonical fusion partners such as CD74, EZR or TPM3 demonstrate high ROS1 expression and derive significant benefit from ROS1-targeted TKIs. In contrast, breakpoints in intron 32 or rare fusion partners correlate with inferior outcomes. These findings highlight the value of genomic precision in optimizing TKI therapy and improving patient outcomes in NSCLC. 2️⃣ Sacituzumab Govitecan plus Pembrolizumab in NSCLC The EVOKE-02 study reports encouraging efficacy for sacituzumab govitecan combined with pembrolizumab as 1L therapy in NSCLC without driver mutations. Among patients with PD-L1 ≥ 50%, the ORR reached 66.7% with a median PFS of 13.1 months, suggesting a viable chemo-free approach. These findings warrant continued exploration of ADC and ICI combinations, which may redefine frontline treatment paradigms in advanced NSCLC. 3️⃣ Oligoprogression and Long-Term Outcomes with Osimertinib Real-world data reveal that 37% of patients with EGFR-mutant NSCLC treated with 1L osimertinib experience oligoprogressive disease, which is associated with a longer time to treatment failure and extended OS compared to diffuse progression. This supports a localized management approach for oligoprogressive lesions, potentially prolonging osimertinib efficacy and delaying the need for systemic therapy changes. 💬 How are you integrating precision mapping, ADC-ICI combinations and progression pattern analysis into your NSCLC management strategies? #Oncology #Hematology #LungCancer #NSCLC #TKI #ROS1 #EGFR #ADC #Immunotherapy #PFS #OS #PrecisionMedicine #ClinicalTrials 🙂

"Advances and Challenges in Non-Small-Cell Lung Cancer (NSCLC) Therapy: Targeted, Immunotherapies, and Beyond" Non-small-cell lung cancer (NSCLC) is a prevalent and deadly form of cancer worldwide. Despite recent therapeutic advancements, it remains largely incurable. Targeted therapies and immunotherapies have improved outcomes, but resistance often develops. This review explores current and potential treatments for NSCLC, emphasizing targeted therapies and immunotherapies, while also considering the role of metabolic and combination therapies in the future. NSCLC comprises the majority of lung cancer cases, with adenocarcinoma being the most common subtype. Genetic profiling has led to the identification of actionable mutations, including EGFR, ALK, ROS1, BRAFV600E, and NTRK gene abnormalities, with FDA-approved treatments. Emerging targets encompass ERBB2, MET, RET, KRASG12C, NRG1, and FGFR. Additionally, metabolic and immune targets like KEAP1-NFE2L2, STK11, PD-1, PD-L1, and CTLA-4 hold promise for NSCLC therapy. https://lnkd.in/ggwnJYm3 #MolecularTargets #EGFRMutations #EGFRpL858R #EGFRExon19Deletion #NSCLC #EGFRTKIs #Osimertinib #TKIResistance #ALKRearrangement #ALKTKIs #BRAFV600E #METExon14 #RETGeneRearrangements #NTRKGeneFusions #KRASG12C #HER2Mutations #LungCancerResearch #PrecisionMedicine #TargetedTherapies #cancertreatment