Nature cancer最新文献

N⁶-methyladenosine (m⁶A) represents the most abundant internal RNA modification and a key regulator of gene expression. Although individual m⁶A regulators and sites have been linked to cancer, their transcriptome-wide functional landscape remains undefined. Here we developed an epitranscriptomic screening platform based on targeted m⁶A deposition to identify functional modifications in prostate and lung cancer models. The unbiased screens uncovered 222 m⁶A sites that modulate cell proliferation, predominantly in a cell-type-specific manner. Among them, an m⁶A site within CHD9 emerged as a potent tumor-suppressive modification in prostate cancer. Deposition of m⁶A at this site increased CHD9 protein abundance, suppressed cell proliferation and attenuated xenograft growth. Mechanistically, m⁶A at CHD9 enhances translation through YTHDF1 and YTHDF3, promoting CHD9-MYBBP1A interaction in the nucleoplasm, sequestrating MYBBP1A from the nucleolus and activating CDKN1A (p21)-associated tumor-suppressive signaling. Collectively, our study establishes a scalable framework for functional mapping of the m⁶A epitranscriptome and uncovers a mechanistic link between CHD9 m⁶A modification and tumor suppression, paving the way for systematic exploration of other RNA modifications in cancer.

Trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate, has transformed treatment for HER2-expressing solid tumors. However, heterogeneous intratumoral HER2 expression, particularly high densities of HER2-immunohistochemistry score 0 (HER2-IHC 0) cells, limits its clinical efficacy. Here, we discovered that targeted inhibition of F-box protein FBXL2 elevates HER2 expression on the plasma membrane of HER2-IHC 0 triple-negative breast cancer (TNBC) cells, thereby sensitizing them to T-DXd. Mechanistically, FBXL2 promotes HER2 polyubiquitination at K747 and proteasomal degradation. Notably, small molecules GGTi-2418 and ketoconazole effectively elevate HER2 expression via blocking FBXL2 membrane localization. We further developed lipid nanoparticles (LNPs) to encapsulate GGTi-2418 and ketoconazole, enabling their enrichment in TNBC tumors. Strikingly, GGTi-2418@LNP or ketoconazole@LNP combined with T-DXd induced robust and durable tumor regression in HER2-IHC 0 TNBC xenograft models in female mice. Together, this study highlights that targeted inhibition of FBXL2 combined with T-DXd may be a viable therapeutic strategy for treating HER2-IHC 0 solid tumors.

The phase 2 SWOG S1512 trial ( NCT02775851 ) was designed to evaluate the response to pembrolizumab (anti-PD-1) in individuals with desmoplastic melanoma. Here we report the results of cohort A of the trial, evaluating the pathological complete response (pCR) rate of neoadjuvant PD-1 blockade in surgically resectable desmoplastic melanoma. Secondary endpoints included clinical response rate, overall survival and toxicities. Twenty-eight eligible individuals with resectable desmoplastic melanoma received intravenous pembrolizumab (200 mg) every 3 weeks three times, followed by excision. Tissue samples before treatment, at 3-5 weeks after treatment initiation and at the time of surgery were reviewed. The primary endpoint of pCR rate by local pathological review was 71% (95% confidence interval, 51-87%; P < 0.001), which met the prespecified endpoint. There were two (7%) grade 3 treatment-related adverse events. At three years of follow-up, four participants have died, none known to be from melanoma or adverse events. In conclusion, neoadjuvant pembrolizumab in individuals with resectable desmoplastic melanoma results in a high pCR rate with acceptable safety profile. Clinicaltrials.gov: NCT02775851 .

Precision healthcare aims to tailor disease prevention and early detection to individual risk. Prostate cancer screening may benefit from genomics-informed approaches. We developed and validated the P-CARE model, a prostate cancer risk prediction tool combining a polygenic score, family history and genetic ancestry, using data from over 585,000 male participants in the Million Veteran Program. The model was externally validated in diverse cohorts and implemented via a blended genome-exome assay for clinical use. Here we show that the P-CARE model identifies clinically meaningful gradients of prostate cancer risk among men, with higher scores associated with increased risk of any, metastatic and fatal prostate cancer. The model is now being used in a clinical trial of precision prostate cancer screening. This work demonstrates the potential for genomics-enabled health systems to improve prostate cancer screening and prevention in men. ClinicalTrials.gov registration: NCT05926102 .

Glucagon-like peptide-1 (GLP-1) medicines reduce food intake, body weight, insulin resistance and inflammation, thus improving outcomes for people with type 2 diabetes and obesity and potentially contributing to decreased cancer incidence. GLP-1 medicines acting through weight loss-dependent and weight loss-independent mechanisms hold potential for suppression of tumorigenesis and reduction of rates of obesity-associated cancer. In this Perspective, we summarize data on cancer incidence from trials and registries in individuals with type 2 diabetes, describe the actions of GLP-1 medicines on preclinical cancer models and highlight possible direct and indirect mechanisms linking GLP-1R signaling to cancer development and progression.