KRAS G12

P1, N=171, Recruiting, Boehringer Ingelheim | N=94 --> 171 | Trial primary completion date: Jun 2028 --> Feb 2029

Our findings highlight the functional heterogeneity of myCAFs and identify TAGLN-expressing myCAFs as critical mediators of tumour progression, providing evidence that targeting stromal TAGLN may represent a promising therapeutic strategy for PDAC.

Gastric tumors can bypass niche dependence by acquiring KRAS-MAPK-SMAD2/3-driven epithelial WNT secretion. Targeting this axis-through MAPK inhibition, SMAD2/3 blockade, or suppression of WNT secretion-may represent a therapeutic vulnerability in gastric cancer and other KRAS-high malignancies.

We outline mechanisms of action, clinical efficacy, and limitations of FDA-approved tyrosine kinase inhibitors (TKIs) and emerging agents, with emphasis on resistance pathways, both on-target and bypass-mediated, observed during treatment with drugs such as osimertinib, crizotinib, sotorasib, and entrectinib. The role of next-generation sequencing (NGS), liquid biopsy, and comprehensive biomarker profiling in guiding personalized therapy selection is also discussed, along with strategies for sequential therapy and rational combination approaches.

There was no difference between KRASm G12C and KRASwt patients in terms of ORR (48% vs. 49%; p = 0.961) and DCR (86% vs. 84%; p = 0.903), nor when comparing KRASm to KRASwt in terms of OS (p = 0.64), PFS (p = 0.28), TTLR (p = 0.26), and TTDR (p = 0.3), with no impact after adjustment for durvalumab. KRAS G12C mutation compared to KRAS wild-type did not affect response to chemoradiotherapy, and KRAS mutations compared to KRAS wild-type were not associated with worse survival in unresectable stage II or III NSCLC treated with chemoradiotherapy.

Our case and related literature review suggest that the multiplex genetic mutation-detection assay should be considered for patients with LCNEC. Furthermore, it also suggests that biomarkers which enable us to distinguish patients who are likely to harbor driver gene alterations are required in near future.

We present a detailed protocol for isolating high-quality single-cell suspensions from both healthy and tumor-bearing murine lung tissue. This protocol can be applied to scRNA-seq, flow cytometry analysis, and primary cell isolation.

Mechanistically, cancer cell derived LIF facilitates an immunosuppressive, pro-tumorigenic state. Importantly, pharmacological targeting of the CREB-LIF signaling axis between cancer cells and macrophages, using a CREB-specific inhibitor (CREBi), significantly suppresses tumor growth and sensitizes PDAC to immunotherapy, highlighting the therapeutic potential of this treatment combination to improve outcomes in this aggressive disease.

Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options.

Specific emphasis is also placed on intracranial activity and the use of sotorasib in special subgroups, including frail patients and those with comorbidities, providing a practical framework for daily clinical practice. The objective is to offer evidence-based guidance to facilitate treatment personalization and improve clinical outcomes in this complex patient population.

Knockdown of RCC1 in pancreatic cancer cells restored SIRT3 expression and impaired tumor formation in vivo. Overall, our study has revealed a previously unrecognized mechanism by which oncogenic KRAS promotes tumor development through down-regulation of the SIRT3-mediated tumor suppression pathway, and has also identified RCC1 as a potential therapeutic target for treatment of cancer patients with KRAS mutations.

Histopathological evaluation may aid risk stratification alongside KRAS status. Prognostic assessment in clinical settings should take both TNM staging and KRAS status into account.