Cancer research最新文献

Resistance remains a key issue limiting the clinical benefit from RAS-targeting therapeutic agents and necessitates combination approaches. Here, we identified persistent mTORC1 activity in preclinical KRAS-mutant non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models as a frequent, nongenetic driver of inherent and adaptive resistance to RAS inhibition. This vulnerability was targetable with the farnesyl transferase inhibitor darlifarnib (KO-2806), which blocks mTORC1 activation via RHEB while sparing mTORC2 to limit associated toxicities. The addition of KO-2806 to NSCLC or CRC tumors progressing on mutant-selective RAS inhibitors led to rapid and durable tumor regression. In contrast, switching from mutant-selective to pan-RAS inhibitor monotherapy resulted in only stasis of NSCLC tumors and had no effect on CRC tumor progression. Further, the addition of KO-2806 rescued sensitivity of progressing tumors to the pan-RAS inhibitor RMC-6236. These results establish mTORC1 as an important mediator of escape from RAS inhibition and highlight KO-2806 as a promising RAS companion inhibitor in patients with prior RAS inhibitor exposure.

Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) exhibit poor clinical outcomes. Metabolic reprogramming of both cancer cells and immune compartments plays a crucial role in shaping the anti-tumor immune response in PDAC. DM-induced metabolic alteration may disrupt the intricate crosstalk between immune cells and tumor-associated immune factors, profoundly influencing PDAC progression. Here, we performed an integrated, spatially resolved multi-omics study to investigate DM-associated, cell-specific metabolic remodeling within the PDAC tumor microenvironment. DM influenced interactions between tumor cells and immune cells, which accelerated PDAC growth in both humans and mice. PDAC patients with DM exhibited higher tumor-stage, poorer differentiation, and worse outcomes. Spatial metabolic and transcriptional profiling revealed that SREBP2-dependent cholesterol biosynthesis exacerbated PDAC progression. Increased cholesterol biosynthesis promoted neutrophil recruitment and accelerated formation of neutrophil extracellular traps (NETs) by stimulating the CXCL1-CXCR1/CXCR2 signaling axis, ultimately promoting PDAC growth. Inhibition of SREBP2, pharmacological blockade of CXCL1, or perturbation of NETs markedly reduced PDAC growth in diabetic mouse models. Together, these multi-omics analyses and follow-up mechanistic studies constitute an integrated approach that elucidates a metabolic mechanism by which diabetes promotes PDAC development by remodeling the tumor immune microenvironment and highlights a potential therapeutic strategy for PDAC with DM.

ARID1A is a crucial subunit of the SWI/SNF chromatin-remodeling complex and is frequently mutated in human cancers. While its tumor-suppressive activity has been ascribed exclusively to SWI/SNF-dependent chromatin remodeling, we established here a SWI/SNF-independent role of ARID1A in safeguarding heterochromatin architecture to silence viral mimicry and restrain immunogenicity in colorectal cancer. ARID1A deficiency triggered viral mimicry and enhanced immunogenicity in both microsatellite stable and instable contexts. Mechanistically, ARID1A interacted with TRIM28 to preserve heterochromatin rigidity. Loss of ARID1A displaced SETDB1 from the TRIM28-containing heterochromatin complex, leading to the reversal of H3K9me3-mediated repression at endogenous retroelement regions. The release of these elements triggered viral mimicry, exemplified by enhanced type I interferon-mediated immune responses. Notably, disrupting the ARID1A-TRIM28 interaction with synthetic peptides induced a viral mimicry phenotype in ARID1A wildtype tumors, converting immunologically "cold" lesions into T-cell-inflamed microenvironments and suppressing tumor growth. Both cytosolic RNA and DNA sensors were required for the ensuing interferon response and for the heightened sensitivity to PD-1 blockade elicited by ARID1A deficiency. These findings thus reveal an unanticipated heterochromatin gatekeeper function of ARID1A that operates outside the SWI/SNF complex and can be exploited to potentiate immune checkpoint therapy activity.

MERTK is a receptor tyrosine kinase predominantly expressed on M2 macrophages that plays a critical role in the clearance of apoptotic cells and maintenance of an immune-suppressive phenotype. M2 macrophages are highly abundant in the tumor microenvironment where they facilitate tumor progression and resistance to immunotherapy. MERTK is also overexpressed in cancer cells, where it can drive cancer survival and metastasis through induction of proliferation and anti-apoptotic signaling programs. Here we developed an antibody-drug conjugate (ADC) that simultaneously targets MERTK-expressing M2 tumor associated macrophages and cancer cells. The ADC comprised the monoclonal antibody RGX-019 that binds human MERTK, combined with a monomethyl auristatin E (MMAE) toxic payload. The unconjugated antibody had intrinsic activity to suppress M2 cytokine expression by macrophages, block in vitro colony formation of cancer cells, and inhibit in vivo tumor growth and metastasis. When MMAE was conjugated to the antibody, the ADC exhibited superior in vitro cytotoxicity and in vivo anti-tumor efficacy in MERTK-expressing tumors. Tumor growth inhibition in humanized mice was associated with depletion of tumor-associated M2 macrophages. Furthermore, unlike other MERTK-targeting small molecules or antibodies, no retinal toxicity of RGX-019-MMAE was observed in vivo. These findings reveal that combined therapeutic targeting of MERTK in cancer cells and M2 macrophages offers enhanced opportunities for anti-tumor efficacy in a wide range of MERTK-expressing tumors.