The AACR Annual Meeting 2025 is set to unveil groundbreaking advancements in the fight against non-small cell lung cancer (NSCLC). This year’s conference will spotlight emerging therapies, novel biomarkers, and cutting-edge research aimed at improving early detection, treatment efficacy, and patient outcomes. From combination strategies for EGFR-Mutated NSCLC to advancements in KRAS-Mutated NSCLC, the latest discoveries could reshape the NSCLC treatment landscape. In this blog, we’ll break down the most exciting highlights from AACR 2025 and explore their potential impact on patients, clinicians, and the future of lung cancer care, created by Ferma Congress’ new Insights module.
Innovative Combination Strategies for EGFR-Mutated NSCLC: Insights from AACR 2025
Overview: The AACR 2025 conference presented several promising combination strategies for treating EGFR-mutated non-small cell lung cancer (NSCLC). These strategies focus on overcoming resistance to EGFR inhibitors, enhancing therapeutic efficacy, and optimizing personalized treatment plans. Key combinations include targeting c-Myc interactions, integrating VEGFR2 antagonists, and leveraging immune checkpoint inhibitors.
- Targeting c-Myc to Overcome Resistance: The study highlighted the efficacy of SGI-1027, a specific inhibitor of MKK3/c-Myc interaction, in overcoming acquired resistance to osimertinib in EGFR-mutated NSCLC. SGI-1027, combined with osimertinib, significantly decreased survival of resistant cells and enhanced apoptosis. In vivo, the combination suppressed tumor growth more effectively than either agent alone, indicating a potent strategy to combat resistance. 1
- Ramucirumab and Osimertinib Synergy: The phase II RAMOSE trial demonstrated that combining osimertinib with the VEGFR2 antagonist ramucirumab improved progression-free survival (PFS) compared to osimertinib monotherapy. Patients with lower EGFR variant allele frequency (VAF) at baseline had significantly longer PFS and overall survival (OS), suggesting that liquid biopsy could guide personalized therapy. 2
- Immune Evasion and Combination Therapies: A novel mouse model of EGFR-mutant NSCLC revealed insights into immune evasion mechanisms. The model showed early cytotoxic immune activity followed by Treg-mediated suppression, suggesting potential therapeutic targets. This model can be used to study the impact of different EGFR TKIs and their combinations with immunotherapeutic modalities, aiming to optimize treatment strategies. 3
Unveiling the Complexities of KRAS-Mutated NSCLC: Latest Research Insights
Overview: Recent studies have delved into the distinct subtypes of KRAS-mutated non-small cell lung cancer (NSCLC), revealing critical insights into their molecular characteristics, resistance mechanisms, and potential therapeutic strategies. These findings are pivotal for advancing personalized treatment approaches and improving patient outcomes.
- Impact of KRASG12C Oxidation State on Therapeutic Efficacy: Research has shown that the oxidation state of KRASG12C significantly influences its ability to bind covalent inhibitors, such as AMG510 (Sotorasib). Oxidation of KRASG12C at Cys12 impacts inhibitor engagement and therapeutic outcomes, with resistance arising in approximately 60% of treated patients. This study highlights the need to evaluate KRASG12C oxidation state to optimize treatment strategies and address resistance mechanisms. 1
- Synergistic Effects of KRAS and HDAC6 Inhibitors: A combination of KRAS inhibitors and HDAC6 inhibitors has demonstrated a synergistic response in KRAS-driven NSCLC cell lines. This combination significantly reduces migration rates and colony formation compared to single drug treatments. Enhanced sensitivity to this drug combination was confirmed in three-dimensional cell cultures, suggesting that HDAC6’s regulation of epithelial-to-mesenchymal transition (EMT) may help overcome resistance to KRAS inhibitors. 2
- Distinct Co-Mutation and Resistance Patterns in KRAS-Mutated NSCLC: Studies have identified unique co-mutation profiles and resistance mechanisms among various KRAS-mutated NSCLC subtypes. For instance, KRAS mutations were highest in non-V1V3 subtypes, with distinct resistance-related mutations such as MET amplification in V1 and EGFR mutations in non-V1V3 and V3 subtypes. Tumor mutational burden (TMB) analysis revealed differential responses to immunotherapy among EML4-ALK subtypes, with V3 patients showing a higher proportion of TMB-H. These findings support personalized treatment strategies and prognostic assessments for NSCLC patients with KRAS mutations. 3
- Role of miR-101-3p/CALCRL/NEAT1 Axis in Tumor Progression: The miR-101-3p/CALCRL/NEAT1 axis has been identified as a novel regulatory network in KRAS-mutated NSCLC. miR-101-3p downregulation correlates with increased expression of CALCRL and NEAT1, promoting tumor progression. Restoration of miR-101-3p suppresses tumor cell proliferation, induces ROS accumulation, impairs mitochondrial function, reduces ATP levels, and triggers apoptosis. These findings highlight miR-101-3p as a promising therapeutic target for KRAS-mutated NSCLC. 4
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