Khoury, S. E. | Search bioRxiv

bioRxiv2026

KRAS inhibition is an effective therapy for appendiceal adenocarcinoma

BackgroundAppendiceal adenocarcinoma (AA) is a rare cancer with limited treatment options. KRAS is the most commonly mutated gene in AA and a promising therapeutic target, but its preclinical and translational relevance in AA remains unclear. MethodsWe evaluated KRASG12D-specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRASmut organoid and orthotopic PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. Clinical outcomes were also assessed in six heavily pre-treated AA patients treated with KRAS inhibitors. ResultsMRTX1133 was highly effective for KRASG12D organoids (IC50=4.1 nM); both KRASG12D and KRASG12V organoids were sensitive to RMC-6236 (IC50=4.4 nM vs 0.5 nM, respectively). In orthotopic PDX models of peritoneal carcinomatosis from AA, MRTX1133 significantly reduced tumor growth in the KRASG12D model TM00351, and RMC-6236 reduced tumor growth in KRASG12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Sets Enrichment Analysis (GSEA) revealed significant downregulations of E2F targets (NES=-1.9, p-adj=0.06) and the newly developed RAS/ERK (NES=-2.3, p-adj=0.06) gene set, consistent with the observed decrease in cell proliferation. There was marked upregulation of EMT (NES=2.7, FDR<0.001) and TGF-{beta} signaling (NES=2.3, FDR=0.004) in remaining tumor cells, suggesting these pathways could confer resistance. scRNA-seq analysis of TME showed dramatic shifts in cancer-associated fibroblasts (CAFs), with KRAS inhibition driving a shift from normal fibroblasts to inflammatory CAFs, and upregulation of interferon alpha and gamma pathways, suggesting that KRAS inhibition can activate innate immune response in the setting of peritoneal metastases. In a cohort of 6 heavily pre-treated patients with AA treated with KRAS inhibitors (1 G12D, 3 G12C, 2 pan-KRAS), all had biochemical response based on CEA/Ca19-9 or ctDNA and clinical benefit by RECIST criteria (1 CR, 1 PR, 4 SD). ConclusionsWhile effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of EMT and TGF-{beta} pathways may mediate resistance in KRASmut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

cancer biology↗

bioRxiv2023

Microbiome remodeling through bacterial competition and host behavior enables rapid adaptation to environmental toxins.

Human activity is altering the environment in a rapid pace, challenging the adaptive capacities of genetic variation within animal populations. Animals also harbor extensive gut microbiomes, which play diverse roles in host health and fitness and may help expanding host capabilities. The unprecedented scale of human usage of xenobiotics and contamination with environmental toxins describes one challenge against which bacteria with their immense biochemical diversity would be useful, by increasing detoxification capacities. To explore the potential of bacteria-assisted rapid adaptation, we used Caenorhabditis elegans worms harboring a defined microbiome, and neomycin as a model toxin, harmful for the worm host and neutralized to different extents by some microbiome members. Worms raised in the presence of neomycin showed delayed development and decreased survival but were protected when colonized by neomycin-resistant members of the microbiome. Two distinct mechanisms facilitated this protection: gut enrichment driven by altered bacterial competition for the strain best capable of modifying neomycin; and host avoidance behavior, which depended on the conserved JNK homolog KGB-1, enabling preference and acquisition of neomycin-protective bacteria. We further tested the consequences of adaptation, considering that enrichment for protective strains may represent dysbiosis. We found that neomycin-adapted gut microbiomes caused increased susceptibility to infection as well as an increase in gut lipid storage, suggesting metabolic remodeling. Our proof-of-concept experiments support the feasibility of bacteria-assisted host adaptation and suggest that it may be prevalent. The results also highlight trade-offs between toxin adaptation and other traits of fitness.

evolutionary biology↗