Cancer discovery最新文献

Significance: Our work demonstrates that the bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives colorectal tumorigenesis. This study also offers novel mechanistic insights into catecholamine action in colorectal cancer. Inhibiting the neuro-mesenchymal interaction by TRK blockade could be a potential strategy for treating colorectal cancer.

Mutations in ERBB2 (encoding HER2) occur in 2% to 4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2-mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent antitumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation), thus supporting the ongoing clinical development of zongertinib. Significance: HER2-mutant NSCLC poses a challenge in the clinic due to limited options for targeted therapies. Pan-ERBB blockers are limited by wild-type EGFR-mediated toxicity. Zongertinib is a highly potent and wild-type EGFR-sparing HER2 inhibitor that is active in HER2-driven tumors in the preclinical and clinical settings.

The Imaging and Molecular Annotation of Xenografts and Tumors Cancer Grand Challenges team was set up with the objective of developing the "next generation" of pathology and cancer research by using a combination of single-cell and spatial omics tools to produce 3D molecularly annotated maps of tumors. Its activities overlapped, and in some cases catalyzed, a spatial revolution in biology that saw new technologies being deployed to investigate the roles of tumor heterogeneity and of the tumor micro-environment. See related article by Stratton et al., p. 22 See related article by Bhattacharjee et al., p. 28 See related article by Goodwin et al., p. 34.

Understanding tumor heterogeneity is a major challenge that was recognized as one of the first Cancer Grand Challenges, with a call to provide solutions to visualize tumor heterogeneity. The Rosetta team took on this challenge, exploiting advances in spatial-omics approaches centered around mass spectrometry imaging to map tumor heterogeneity at the cellular and molecular scales with different levels of resolution. See related article by Bressan et al., p. 16 See related article by Stratton et al., p. 22 See related article by Bhattacharjee et al., p. 28.

Small cell lung cancer (SCLC) and pulmonary carcinoid tumors are traditionally seen as unrelated, with SCLC linked to smoking and characterized by biallelic loss of RB1 and TP53 and rapid progression. Rekhtman and colleagues upend these assumptions by discovering an "atypical" SCLC that arises in nonsmokers with intact RB1 and TP53 loci, chromothripsis-induced oncogene amplifications on extrachromosomal DNA, and frequent synchronous carcinoid tumors. See related article by Rekhtman et al., p. 83.

Small cell lung carcinoma (SCLC) is a highly aggressive malignancy that is typically associated with tobacco exposure and inactivation of RB1 and TP53 genes. Here, we performed detailed clinicopathologic, genomic, and transcriptomic profiling of an atypical subset of SCLC that lacked RB1 and TP53 co-inactivation and arose in never/light smokers. We found that most cases were associated with chromothripsis-massive, localized chromosome shattering-recurrently involving chromosome 11 or 12 and resulting in extrachromosomal amplification of CCND1 or co-amplification of CCND2/CDK4/MDM2, respectively. Uniquely, these clinically aggressive tumors exhibited genomic and pathologic links to pulmonary carcinoids, suggesting a previously uncharacterized mode of SCLC pathogenesis via transformation from lower-grade neuroendocrine tumors or their progenitors. Conversely, SCLC in never-smokers harboring inactivated RB1 and TP53 exhibited hallmarks of adenocarcinoma-to-SCLC derivation, supporting two distinct pathways of plasticity-mediated pathogenesis of SCLC in never-smokers. Significance: Here, we provide the first detailed description of a unique SCLC subset lacking RB1/TP53 alterations and identify extensive chromothripsis and pathogenetic links to pulmonary carcinoids as its hallmark features. This work defines atypical SCLC as a novel entity among lung cancers, highlighting its exceptional histogenesis, clinicopathologic characteristics, and therapeutic vulnerabilities. See related commentary by Nadeem and Drapkin, p. 8.

Significance: Clinically available KRAS* inhibitors and IO agents alleviated the immunosuppressive tumor microenvironment in PDAC. Profound tumor regression and prolonged survival in an autochthonous PDAC model provide a compelling rationale for combining KRAS* inhibition with IO agents targeting multiple arms of the immunity cycle to combat PDAC.