KRAS wild-type

P2, N=29, Terminated, Aurigene Discovery Technologies Limited | N=90 --> 29 | Trial completion date: May 2027 --> Feb 2026 | Recruiting --> Terminated | Trial primary completion date: Sep 2026 --> Feb 2026; Patient recruitment problems.

KSR1 knockdown did not substantially affect ppERK responses to Type I½ RAF inhibitor (Encorafenib) in both cell types, whereas ppERK sensitivity slightly decreased for Type II RAFi (TAK-632) in MCF7 cells, aligning with simulations. The efficacy of MEKi (Cobimetinib) slightly increased in MCF7 cells following KSR1 knockdown but slightly decreased in PSN1 cells where higher MEKi concentrations were required to suppress ERK signaling, as predicted by the model. Our computational models predict, and experiments validate that in RAS-mutant cells, two conformation-specific RAF inhibitors used in combination suppress the ERK pathway more effectively than a combination of MEK and RAF inhibitors irrespective of KSR1 levels.

Patients with BRAF-mutated tumors may benefit from extended lymphadenectomy. Future randomized trials should evaluate biomarker-driven surgical strategies in CC.

In an HCT116 xenograft model, oral administration of SL43 (20 and 40 mg/kg) also significantly suppressed tumor growth (TGI = 57.2% and 74.9%, respectively), outperforming MRTX0902 (60 mg/kg, TGI = 47.1%) with no observable systemic toxicity. In conclusion, SL43 represents a potent and orally bioavailable SOS1 inhibitor that effectively suppresses KRAS signaling and exerts strong antitumor efficacy, highlighting its potential as a promising candidate for KRAS-mutant colorectal cancer.

The study underscores the importance of integrating NGS-based molecular testing with PD-L1 evaluation for personalised management of NSCLC. Distinct patterns of PD-L1 expression across molecular subtypes, particularly lower in EGFR-mutated tumours and higher in KRAS-mutated tumours, underscore the need for tailored therapeutic strategies and informed sequencing of targeted therapies and immunotherapies.

P1/2, N=90, Recruiting, Universita Degli Studi Di Padova | Not yet recruiting --> Recruiting

Lung adenocarcinomas are characterized by a high prevalence of targetable alterations, with KRAS G12C representing the most frequent alteration. KRAS mutation status showed limited prognostic relevance. These findings support routine molecular testing and integration of genomic and clinical data to guide personalized treatment.

In addition, 089 exhibited good tolerability in a nude mouse HCT-116 xenograft model, but it was less effective at a dose of 40 mg/kg compared with Apremilast at a dose of 30 mg/kg in 8-s day's assay. While 089 had lower in-vivo efficacy than apremilast, its novel 3-aminoisoquinoline scaffold and high tolerability make it a superior candidate for further optimization.

In first-line ICI-treated stage IV NSCLC, KRAS-KEAP1 co-mutation, not KRAS or KEAP1 alone, identifies patients at high risk of early failure, whereas BRAF was associated with longer TTF. These findings highlight the importance of co-mutation profiling and warrant prospective validation with integrative models incorporating PD-L1 and TMB.

This study is the largest longitudinal analysis of KRASM testing conducted in Australia, with significant improvement in testing rates seen over the time period. Rates of KRASM and characteristics of Australian KRAS mt patients correspond with published literature.

Incorporating a structured diagnostic algorithm that recognizes rare subtypes and integrating comprehensive genomic profiling into routine practice represents a paradigm shift from non-stratified to mechanism-driven therapy in pancreatic cancer. This narrative review summarizes the clinicopathological characteristics, molecular landscapes, and therapeutic opportunities of rare PDAC subtypes, highlighting how precision medicine can reshape prognosis and treatment in a historically hard-to-treat disease.

Emerging immunotherapies targeting Claudin18.2 and CXCR4 offer hope to overcome tumor resistance. Together, these strategies underscore the promise of molecular stratification, synthetic lethality, and novel targets to improve pancreatic cancer survival.