KRAS mutations promote PD-L1-mediated immune escape by ETV4 in lung adenocarcinoma
Jia D, Wang P, Zheng S, et al. Transl Oncol. 2025;61:102525.
Summary. Analyzing KRAS-mutant and KRAS-wildtype lung adenocarcinoma (LUAD) cell lines and tissue samples, researchers found that programmed death-ligand 1 (PD-L1) expression was elevated in KRAS-mutant LUAD compared to KRAS-wildtype LUAD. ETV4 was identified as the key transcription factor regulating PD-L1 expression in KRAS-mutant LUAD. ETV4 expression was upregulated in KRAS-mutant versus KRAS-wildtype LUAD, and KRAS knockdown resulted in decreased ETV4 expression, thereby indicating that KRAS mutation induced ETV4 upregulation. ETV4 knockdown led to significantly decreased PD-L1 expression, and ETV4 was found to bind to the promoter region of PD-L1, thus indicating that ETV4 regulated PD-L1 expression in KRAS-mutant LUAD. In vitro analyses showed that PD-L1-mediated immune escape via ETV4 was facilitated by KRAS-mutant cells.
* PMID: 40946586, PMCID: PMC12496248
Impact of KRAS G12C mutation on the efficacy of chemoradiotherapy in patients with unresectable stage II or III non-small cell lung cancer
Cabon J, Lerouge D, Thureau S, et al. Front Oncol. 2025;15:1675825.
Summary. In this retrospective study, researchers evaluated the efficacy of chemoradiotherapy (CRT) among patients with unresectable stage II or III non-small cell lung cancer (NSCLC) with KRAS G12C mutations. Among 267 patients, 73 harbored KRAS mutations, of whom 42 had KRAS G12C mutations. Seventy-five percent of patients (n=200) received concomitant CRT. Objective response rate (ORR) was similar among the KRAS G12C mutation and KRAS wildtype groups (48% vs. 49%, p=0.961). ORR did not significantly differ between KRAS G12C and non-G12C mutation groups (48% vs. 45%). Neither overall survival (OS) nor progression-free survival (PFS) significantly differed between KRAS G12C mutation, KRAS non-G12C mutation, and KRAS wildtype groups. Additionally, time to either distant or local relapse did not significantly differ between patients with and without KRAS mutations.
* PMID: 41395604, PMCID: PMC12695551
Dipeptidyl peptidase 4 restoration facilitates antitumor immunity in KRAS–LKB1-mutant lung cancer
Tenma T, Yoshida R, Yanada H, et al. Cancer Res Commun. 2025;5(12):2175–2185.
Summary. Researchers analyzed the impact of dipeptidyl peptidase 4 (DPP4) restoration in KRAS/LKB1-mutant NSCLC. DPP4 reconstitution in KRAS/LKB1-mutant cells increased DPP4 expression and activity and significantly induced immune-related signatures, including natural killer (NK) cell activation. NK and T cell migration were enriched with DPP4 reconstitution. In a syngeneic murine model, DPP4 reconstitution alone did not affect tumor growth compared to controls without reconstitution. However, DPP4 reconstitution significantly reduced tumor growth upon anti-programmed cell death protein 1 (PD-1) treatment compared to controls. These findings suggest that DPP4 might be a future target to overcome immune resistance in KRAS/LKB1-mutant NSCLC.
* PMID: 41283988, PMCID: PMC12709056
Prognostic and predictive implications of tumor suppressor gene alterations in non-small cell lung cancer
Sposito M, Belluomini L, Nocini R, et al. Sci Rep. 2025;15(1):34807.
Summary. Researchers evaluated the prognostic and predictive values of various tumor suppressor gene alterations in advanced NSCLC. Data from 201 patients were included for analysis. After adjustment, STK11 and KEAP1 alterations were significantly associated with decreased OS (adjusted hazard ratio [aHR]: 2.89, p<0.001; aHR: 2.09, p=0.043, respectively). Patients with KRAS G12C mutations and KRAS-wildtype patients showed similar OS. Patients with KRAS G12C mutations had prolonged median OS compared to patients with other KRAS mutations (42 vs. 14 months). Harboring both KRAS and STK11 alterations was associated with significantly reduced OS compared to patients with wildtype or single KRAS or STK11 alterations (aHR: 3.94, p<0.001); similarly, KRAS/KEAP1 (aHR: 2.35, p=0.042), STK11/TP53 (aHR: 2.55, p=0.008), and STK11/KEAP1 (aHR: 2.70, p=0.022) coalterations were associated with worse OS.
* PMID: 41053251, PMCID: PMC12500927
KRAS mutation subtypes in metastatic non-small cell lung cancer
Aytac A, Demir B, Balcik OY, et al. Am J Cancer Res. 2025;15(7):3188–3196.
Summary. Among 101 patients with KRAS-mutant metastatic NSCLC, 69 (68.3%) harbored KRAS G12C mutations and 32 (31.7%) harbored other KRAS mutations. Common sites of metastases in both groups included bone, brain, and lung. The most common mutations in the KRAS non-G12C group were KRAS G12V (14.8%) and G12D (5.9%). Most patients received first-line cytotoxic chemotherapy, and at median follow-up of 15.3 months, ORR was 47.5% in the KRAS G12C group and 48.3% in the KRAS non-G12C group (p=0.657). Median PFS and OS were similar between KRAS G12C and KRAS non-G12C groups (p=0.852 and 0.201, respectively).
* PMID: 40814365, PMCID: PMC12344164
Strategies for improving biomarker testing rates in non-small cell lung cancer in North America: a scoping review
Salazar AS, Noy J, Reynolds JM, et al. J Thorac Dis. 2025;17(10):9225–9239.
Summary. Here, researchers identified barriers to NSCLC biomarker testing in the United States (US) and Canada. Operational barriers include time-related constraints, such as delays in turnaround time, and lack of sufficient tissue samples. Implementing streamlined reflex testing and utilizing advanced technologies are potential solutions. Barriers related to communication and knowledge include challenges in care coordination and gaps in provider knowledge or awareness. Potential solutions include providing education/continuous learning opportunities and implementing multidisciplinary tumor boards. Access and financial–related barriers include inadequate funding and insurance coverage and infrastructure constraints. Securing funding and improving reimbursement and coverage policies would address these barriers.
* PMID: 41229828, PMCID: PMC12603450
Efficacy and prognostic analysis of chemo-immunotherapy after TKI resistance in EGFR-mutant non-small cell lung cancer with TP53 or KRAS comutations
Nie Y, Song C, Wu K, et al. Front Immunol. 2025;16:1684089.
Summary. Among 168 patients with EGFR-mutant NSCLC who received first-line epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) treatment, patients with EGFR mutation alone (n=36) had a median PFS of 14.1 months after first-line EGFR-TKI therapy, which was significantly longer than that of patients with EGFR/KRAS (n=52, 10.9 months) or EGFR/TP53 (n=80, 10.4 months) comutation (p<0.0001). All patients received chemotherapy plus immunotherapy following progression on EGFR-TKI therapy; median PFS following second-line treatment was longer in the EGFR/KRAS (5.0 months) and EGFR/TP53 (5.2 months) comutation groups compared to the EGFR mutation alone group (3.9 months; p<0.0001). According to multivariate analysis, EGFR/KRAS comutation (HR: 2.10, p=0.002) and EGFR/TP53 comutation (HR: 1.85, p=0.004) were associated with higher hazard of progression.
* PMID: 41306958, PMCID: PMC12645222