KRAS mutation

Those treated with PD-1/PD-L1 inhibitors (Pembrolizumab) had limited benefit, with a median overall survival of 4.1 ± 2.8 months...Comprehensive genomic profiling may help refine understanding of tumour biology and potentially inform treatment decisions. Larger studies are needed to validate these findings, but integrating genomic, pathologic, and clinical data may advance personalized therapy for these patients.

Patients with lung-only metastases had a better OS than others, were more often women, and harbored less KRAS mutations. Our results argue in favor of PDAC with specific characteristics, especially a better prognosis, possibly further enhanced by the possibility to perform local treatments, and less detection of ctDNA.

The triple combination of SHP2/MEK1/2 inhibition and the ferroptosis-inducing natural compound withaferin A suppressed tumor progression in an endogenous PDAC tumor model in vivo. Our study offers a metabolic leverage point to reinforce RAS pathway interference for targeted PDAC treatment.

Immunotherapy constitutes the cornerstone of first-line therapy for KRAS-mutant NSCLC. Within this framework, PD-(L)1 monotherapy may be appropriate for carefully selected patients with high PD-L1 expression, whereas chemoimmunotherapy can extend benefit to broader subgroups; escalation with anti-VEGF or anti-CTLA-4 agents appears clinically promising and merits biomarker-driven prospective evaluation. KRAS G12C inhibitors are effective in later lines, while treatment options for non-G12C disease remain limited.

P1/2, N=140, Recruiting, InxMed (Shanghai) Co., Ltd. | Trial completion date: Dec 2026 --> Dec 2028 | Trial primary completion date: Dec 2025 --> Dec 2027

P1, N=574, Recruiting, Revolution Medicines, Inc.

P3, N=400, Recruiting, InxMed (Shanghai) Co., Ltd. | Not yet recruiting --> Recruiting

BRAF-mut PTC is associated with a pro-inflammatory TME milieu compared to BRAF-wt PTC. However, in this limited data set, treatment choice was not associated with differences in OS in BRAF-mut PTC.

KRAS inhibitors, including KRAS G12D inhibitor MRTX1133, are promising therapeutics against KRAS-mutated pancreatic ductal adenocarcinoma (PDAC), but drug resistance limits their efficacy. Our study reveals that robust induction of apoptosis using a combination of BCL-xL PROTAC degrader and an mTOR inhibitor, significantly enhances MRTX1133 efficacy in PDAC models without increasing toxicity to normal tissues.

The kinases PAK1 and PAK2 shield RAS from LZTR1-dependent degradation by phosphorylating T148, and targeting PAK1/2 activity improves RAS-directed therapy. Collectively, our findings reveal a novel regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.

Accordingly, this review summarizes relevant reasons underlying diverse resistant mechanisms in KRAS G12C-mutated NSCLC, with an emphasis on deciphering the mechanism of tumor suppressor gene (TSG) alterations serving as key mediators linking oncogenic KRAS dependency to therapeutic resistance. Our research continued to discuss relevant preclinical models to facilitate the advancement of the study of these resistance mechanisms.

This case underscores the diagnostic challenges of MLA, particularly its ability to masquerade as low-grade or high-grade serous carcinoma on morphology, including cytology, frozen, and permanent sections. We compare the cytologic, histologic, immunophenotypic, and molecular features of MLA and serous carcinoma, highlighting the importance of thorough evaluation to avoid the pitfall of morphology-only diagnosis.