Aug 2026· Annals of Oncology· 0 citations· 54 references
Medicine
TL;DR
RAS alterations mediate resistance to targeted agents in approximately 10% of oncogene-driven lung cancer, and Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.
Abstract
Background
Despite the dramatic activity of next generation targeted therapies, most patients with oncogene-driven lung cancers eventually relapse. Novel inhibitors are particularly active against on-target resistance, fostering the emergence of off-target resistance mechanisms. The current clinical development of RAS inhibitors hints at their potential role in overcoming off-target resistance mediated by RAS alterations.
PATIENTS AND
Methods
Using tissue and liquid biopsies, we assessed resistance mechanisms to first-line osimertinib in patients with EGFR-mutant lung cancer, and to ALK-, MET-, ROS1-, and RET- inhibitors, for a total of 590 patients. We established two patient-derived models with acquired KRAS mutations obtained at osimertinib progression, enabling in vitro and in vivo functional experiments.
Results
Among 312 patients progressing on first-line osimertinib, we observed a major complementary role of tissue and liquid biopsies in identifying resistance mechanisms. We identified RAS alterations in 35 of 312 patients (11.2%), with an enrichment in KRAS G12D (n = 10) and a paucity of KRAS G12C (n = 1) mutations. In patients with ALK-positive disease (n = 148), RAS alterations were more common at resistance to lorlatinib compared to second-generation inhibitors (14.7% vs 5%, p = 0.0444). Across MET-, ROS1-, and RET-driven lung cancers at progression to targeted agents, RAS alterations were detected in 7-16% of the cases. In the two patient-derived models established at osimertinib resistance with acquired KRAS mutations (G12D and G12R, respectively), we tested the combinatorial effect of osimertinib with either the selective KRAS G12D inhibitor zoldonrasib or the pan-RAS inhibitor daraxonrasib. Both combinations demonstrated marked synergistic activity in vitro and in vivo.
Conclusions
RAS alterations mediate resistance to targeted agents in approximately 10% of oncogene-driven lung cancer. Rational combinations with novel RAS inhibitors are effective in preclinical models, providing the basis for their clinical investigation and extending the paradigm of precision oncology.
This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.
Xizhi Zha· Theoretical and Natural Scie...· 0 citations
Ras/MAPK alterations drive roughly 40% of human cancers which vary in phenotype, aggressiveness, and response to therapy. This thesis asks how oncogenic Ras/MAPK signaling interacts with distinct components of the tumor microenvironment to drive therapy resistance in two cancer types. The negative regulator of Ras, Neurofibromin 1 (NF1), is altered in about 20% of tubo-ovarian high-grade serous carcinomas (HGSC). We use in vitro and in vivo models of ovarian cancer to study how cell-cell interactions between adipocytes and cancer cells impact therapy response. NF1 alteration exacerbates adipocyte-mediated resistance to standard-of-care chemotherapy. Downstream of Ras, activating mutations in the BRAF kinase are present in over half of cutaneous melanoma cases. Specifically, BRAF^[V600E] hyperactivates downstream MAPK signaling, which is the target of several generations of small-molecule inhibitors. MAPK-targeted therapies show initial efficacy in patients, but acquired resistance is a major clinical threat. Focusing on the role of the immune compartment in treatment-refractory melanoma, we show that targeting the novel immune checkpoint, P-selectin glycoprotein ligand-1 (PSGL-1), delays relapse to BRAF/MEK-targeted therapy in pre-clinical models. Combined BRAF/MEK and PSGL-1 targeting provides a durable anti-tumor response through enhanced functionality and a memory-like phenotype in CD8⁺ T cell subsets. Together, these studies address how tumor-cell intrinsic and extrinsic factors interact under the selective pressure of therapy in Ras/MAPK-altered solid tumors. We provide insight on how genetic alterations affect interactions between cancer cells and their environment and how these dynamics reveal resistance mechanisms that can be exploited for therapeutic benefit.
Epidermal growth factor receptor (EGFR) activating mutations are pivotal driver alterations in non-small cell lung cancer (NSCLC), with a markedly higher prevalence in Asian populations, female patients, and never-smokers relative to other subgroups. EGFR tyrosine kinase inhibitors (TKIs) have been established as the first-line standard-of-care therapy for EGFR-mutant NSCLC. The third-generation agent osimertinib significantly improves survival outcomes, with a confirmed median progression-free survival (PFS) of 18.9 months in the first-line setting based on the FLAURA pivotal trial. Nevertheless, acquired resistance universally develops within a finite treatment period, and primary resistance occurs in a subset of patients, collectively constituting the major clinical bottleneck limiting durable therapeutic benefits. EGFR-TKI resistance is characterized by substantial complexity and inter- and intra-tumoral heterogeneity, driven by a spectrum of genetic and non-genetic adaptive mechanisms. Notably, distinct resistance mechanisms differ substantially in clinical actionability, defined as the feasibility of clinical detection, availability of targeted therapeutic options, and potential for clinical translation. Existing review studies mainly categorize EGFR-TKI resistance based on genetic mutation types but fail to integrate clinical practicality, resulting in ambiguous hierarchical logic and limited clinical guiding value. To address this gap, the present review systematically reorganizes and classifies EGFR-TKI resistance mechanisms strictly based on clinical actionability and intervention feasibility, constructing a standardized three-tier hierarchical framework: clinically actionable core resistance mechanisms with mature clinical intervention regimens, potentially actionable auxiliary mechanisms with preclinical evidence but limited clinical validation, and refractory primary resistance mechanisms without routine effective intervention strategies. Specifically, core actionable mechanisms include EGFR on-target secondary mutations and compensatory bypass pathway activation, which are well-validated in clinical cohorts and correspond to mature targeted therapies; potentially actionable mechanisms cover tumor phenotypic transformation, metabolic reprogramming, epigenetic modification, autophagy dysregulation, and tumor microenvironment abnormalities, all of which are supported by robust preclinical data but lack large-scale prospective clinical verification; refractory primary resistance is attributed to inherent tumor genetic backgrounds and host individual factors that currently cannot be effectively targeted in routine clinical practice. On the basis of this hierarchical classification, we further correlate each tier of resistance mechanisms with corresponding targeted therapeutic strategies, including next-generation EGFR-TKIs, pathway-specific combination targeted therapy, novel translational therapeutics, metabolic intervention, and traditional Chinese medicine (TCM)-derived natural product adjuvant therapy. This study aims to clarify the hierarchical logical relationship of heterogeneous EGFR-TKI resistance mechanisms, provide evidence-based references for individualized post-resistance clinical decision-making, and offer feasible directions for subsequent translational research and therapeutic optimization.
Yujia Zhai, Xilong Zhou, Weiming Zhao et al.· American Journal of Cancer R...· 0 citations
These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy, however, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.
Pasham Uma, Dandotikar Neha, R. Manisha et al.· International Journal of Inn...· 0 citations
This review synthesizes current knowledge on KRAS resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies.
Rawan Salih, F. Sirajudeen, Mohamed Rahmani· Journal of Advanced Research· 0 citations
Direct KRAS inhibition has transformed KRAS G12C–mutated NSCLC from a previously undruggable subtype into a targetable disease, but durable disease control remains an unmet need.
Kohei Eguchi, Yukito Kajita, Muraoka Suguru et al.· Journal of Clinical Question· 0 citations
