CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC

KRAS Mutations Reprogram RNA m6A Modifications to Drive CD73-Dependent Immune Evasion in Colorectal Cancer.

It is found that KRAS mutations remodel the N6-methyladenosine (m6A) epitranscriptome to promote immune evasion and highlight METTL3 as a promising therapeutic target.

RAF1 S257L/S259F hotspot mutations: functional characterization and intrinsic resistance to the RAS(ON) inhibitor daraxonrasib in melanoma.

TFAP2A links drug resistance to antitumor immunity

This work found that BRAF/MEK inhibitors significantly upregulate TFAP2A, and identifies TFAP2A as a shared driver of both targeted therapy resistance and immunosuppression, offering a one-stone-two-bird strategy to overcome drug resistance and elicit antitumor immunity.

Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer

Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications. Kras mutations have been associated with immune suppression in pancreatic cancer. Here the authors show that KRAS targeting with MRTX1133 or Daraxonrasib specifically synergizes with anti-CTLA4, but not other immune checkpoint inhibitors, in inducing tertiary lymphoid structures and promoting anti-tumor immune responses in preclinical pancreatic cancer models.

KRAS mutations as architects of the tumor immune microenvironment: implications for combination therapies

Oncogenic KRAS mutations rank among the most prevalent driver alterations in human malignancies, reaching near-universal frequency (~98%) in pancreatic ductal adenocarcinoma (PDAC) and high prevalence in colorectal cancer (CRC, ~52%) and lung adenocarcinoma (LAC, ~32%). Beyond their canonical roles in promoting cell-intrinsic proliferation and survival through the MAPK/ERK and PI3K/AKT cascades, KRAS mutations actively sculpt a profoundly immunosuppressive tumor microenvironment (TME), which constitutes a major barrier to both targeted therapy and immunotherapy. Through coordinated programs encompassing inflammatory cytokine secretion, downregulation of antigen presentation machinery, tumor-associated macrophage (TAM) reprogramming, myeloid-derived suppressor cell (MDSC) expansion, and PD-L1 upregulation, KRAS-mutant tumors establish robust immune exclusion. These programs are further stratified by co-mutations in STK11 , KEAP1 , and TP53 , which define distinct immune phenotypes ranging from inflamed to profoundly immune-excluded “cold” tumors. The recent approval of covalent KRAS G12C inhibitors, sotorasib and adagrasib, has revealed that targeted KRAS blockade can remodel the TME toward an immunostimulatory state, providing a mechanistic rationale for combining KRAS-directed agents with immune checkpoint blockade, STING agonists, and neoantigen vaccines. This mini-review synthesizes the current knowledge of KRAS-immune crosstalk, highlights existing controversies and research gaps, and evaluates emerging combination strategies designed to convert immune exclusion into durable anti-tumor immunity.

Dual Targeting of FGFR4 and PI3K–mTOR Suppresses Tumor-Associated Phenotypes in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive adaptive signaling plasticity and metabolic reprogramming that contribute to therapeutic resistance. While the PI3K–mTOR pathway is a central regulator of these processes, the role of the FGF19–FGFR4 axis and its interaction with PI3K-mTOR signaling remains incompletely defined in PDAC. This study investigated whether co-targeting FGFR4 and PI3K-mTOR signaling could overcome adaptive pathway reactivation and suppress tumor-promoting phenotypes. PDAC cell lines representing a spectrum of FGFR4 dependence were treated with the selective FGFR4 inhibitor fisogatinib in combination with the clinically relevant PI3K–mTOR inhibitor gedatolisib. Transcriptomic analyses of TCGA data, along with molecular and functional responses, were evaluated. Transcriptomic analysis demonstrated a positive association between FGFR4 and PI3K–mTOR signaling and linked combined pathway components with poorer overall survival. Across heterogeneous PDAC models, combined inhibition reduced viability, clonogenic survival, migration, and cell-cycle progression more consistently than monotherapy. Apoptosis induction was driven principally by fisogatinib and combination treatment, resulting in comparable apoptotic responses across cell lines. Mechanistically, combined inhibition converged on increased 4E-BP1 inhibitory activity, despite compensatory ERK-RSK pathway activation, indicating that adaptive MAPK was insufficient to restore downstream translational output. In FGFR4-dependent cells, the combined inhibition also reduced secretion of the FGFR4 ligand FGF19. The FGFR4 and PI3K–mTOR signaling comprises a partially interconnected network in PDAC that converges on 4E-BP1-dependent translational control. Dual pathway inhibition consistently and additively suppressed tumor-associated phenotypes despite compensatory MAPK activation, with the clearest added benefit over fisogatinib alone in migration, cell-cycle control, and 4E-BP1 modulation, supporting translational regulation as a shared therapeutic vulnerability. These findings provide a preliminary rationale for biomarker-guided strategies targeting FGFR4 and PI3K–mTOR signaling in pancreatic cancer.