Cancer discovery最新文献

Hepatocellular carcinoma presents strong sexual dimorphism, being 2-3 times more frequent in males than in females; however, the role of sex in response to immunotherapies in HCC remains unknown. We demonstrate that NOTCH1, an understudied oncogene in HCC, elicits sexually dimorphic anti-tumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors displayed enhanced anti-tumor immune responses, which, in mice, were mediated by dendritic and T cells. Conversely, females harboring NOTCH1-driven tumors presented immune evasion and resistance to immunotherapies through a defect in DC-mediated priming and activation of CD8+ T cells in mice, which was restored therapeutically with CD40 agonism. Mechanistically, the sexually dimorphic immunity was mediated by genes in the sex chromosomes but not by sex hormones. Together, our study unravels an unexpected association between NOTCH1 and sex in cancer immunity and highlights the potential of restoring the DC-CD8+ T cell axis with CD40 agonism to improve outcomes.

Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. Here, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ~800 cancer cell lines, nominating a poorly studied kinase, PKN2, as a top therapeutic target of the MLS. Co-essentiality relationships, biochemical experiments, and genomic analyses of patient tumors revealed that PKN2 promotes mesenchymal-like cancer growth through a PKN2-SAV1-TAZ signaling mechanism. Notably, pairing genetic PKN2 inhibition with clinically relevant targeted therapies against EGFR, KRAS, and BRAF oncogenes suppresses drug resistance by depleting mesenchymal-like drug-tolerant persister cells. These findings provide evidence that PKN2 is a core regulator of the Hippo tumor suppressor pathway and highlight the potential of PKN2 inhibition as a generalizable therapeutic strategy to overcome drug resistance driven by the MLS across cancer contexts.

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histologic features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies. Significance: Our work reveals robust and durable antitumor activity of the preclinical RAS(ON) multiselective inhibitor RMC-7977 against difficult-to-treat subsets of KRASG12C-mutant NSCLC with primary or acquired RASG12C inhibitor resistance and identifies a conserved mucinous transcriptional state that supports RAS inhibitor tolerance. See related commentary by Marasco and Misale, p. 2018.

The Chinese government has, in recent decades, implemented various administrative laws and regulatory policies to expedite cancer therapeutic development, boosting research and development pipelines for domestic pharmaceutical companies and clinical trials; however, China faces unique challenges given the high prevalence of certain cancer types and distinct disease burdens, some of which are frequently overlooked by international pharmaceutical companies. Given the substantial unmet need for China-specific cancer care, it is crucial to promote the development of innovative pharmaceutical and clinical research in China, with a particular emphasis on addressing tumors most prevalent in its population.

Despite an increasingly detailed understanding of cancer hallmarks at molecular or atomic resolution, most studies, however, fall short of investigating the systemic interactions of cancer with the human body. We propose to investigate the hallmarks of cancer from an organ-wide macroscopic view, discuss the challenges in preclinical and clinical research to study the cross-organ regulation of cancer together with potential directions to overcome these challenges, and foresee how this holistic view may be translated into more effective therapies.

Lung cancer screening via annual low-dose computed tomography has poor adoption. We conducted a prospective case-control study among 958 individuals eligible for lung cancer screening to develop a blood-based lung cancer detection test that when positive is followed by a low-dose computed tomography. Changes in genome-wide cell-free DNA fragmentation profiles (fragmentomes) in peripheral blood reflected genomic and chromatin characteristics of lung cancer. We applied machine learning to fragmentome features to identify individuals who were more or less likely to have lung cancer. We trained the classifier using 576 cases and controls from study samples and validated it in a held-out group of 382 cases and controls. The validation demonstrated high sensitivity for lung cancer and consistency across demographic groups and comorbid conditions. Applying test performance to the screening eligible population in a 5-year model with modest utilization assumptions suggested the potential to prevent thousands of lung cancer deaths. Significance: Lung cancer screening has poor adoption. Our study describes the development and validation of a novel blood-based lung cancer screening test utilizing a highly affordable, low-coverage genome-wide sequencing platform to analyze cell-free DNA fragmentation patterns. The test could improve lung cancer screening rates leading to substantial public health benefits. See related commentary by Haber and Skates, p. 2025.

Gastric cancer remains one of the top cancers in China compared with Western countries, mainly attributed to the high rates of Helicobacter pylori infection. However, recent discoveries on the non-H. pylori gastric microbiome have led to a paradigm shift in our understanding of microbial risk factors driving gastric cancer, which will impact future screening and prevention strategies.