Volume 1 Issue 1, January 2020

Intratumoral genetic heterogeneity of driver somatic mutations is present in a variety of tumor types, yet the extent of heterogeneity is variable. We propose that this variation is a reflection of the inherent biology of a given tumor type, representing the pace of metastatic dissemination and hence clinical disease course.

Norman E. ‘Ned’ Sharpless became director of the US National Cancer Institute (NCI) in 2017. From April 2019, he served as acting commissioner of the US Food and Drug Administration (FDA), and he returned to the NCI in November. Douglas R. Lowy has been the principal deputy director of the NCI since 2010, having also served as acting director twice, most recently in 2019. Nature Cancer spoke with both last fall to learn more about what makes NCI and its leadership tick.

Cancer research in recent years has been marked by significant developments in understanding disease biology and foundational discoveries that have changed clinical practice. Ten cancer researchers take stock of the field, the advances that excite them, key outstanding questions and breakthroughs they anticipate looking forward.

Immunotherapy resistance is associated with poor T cell infiltration into tumors. Tumor-cell-intrinsic oncogenic events that contribute to this defect include Wnt–β-catenin activation. PAK4 is now identified as an upstream modulator of this pathway, thus suggesting the potential of enhancing the efficacy of immunotherapy by targeting this druggable kinase.

Identifying cancer driver mutations is essential to understand disease biology and devise effective therapies, but remains a complex endeavor. A focused analytical approach is now presented that defines driver mutations affecting ubiquitin-mediated proteolysis through machine learning and mining of cancer multi-omics data.

Metastasis competence can be acquired early in tumorigenesis, although its underlying molecular intricacies remain unclear. A recent study provides key information about the function of L1CAM in conferring metastasis-initiation potential and chemoresistance in colorectal cancer by hijacking epithelial regenerative mechanisms.

KRAS mutations are among the most prevalent tumor drivers, but targeting them pharmacologically has been challenging. Recent landmark studies have demonstrated promising clinical results of KRAS^G12C inhibition by using small molecules. Bar-Sagi, and Knelson and Sequist provide their distinct perspectives on this recent tour de force in targeting KRAS^G12C alterations.

The authors identify a population of L1CAM-positive cells that, following loss of epithelial integrity, promote intestinal tissue regeneration and mediate metastasis initiation and chemoresistance in colorectal cancer.

Ribas and colleagues report that inhibition of PAK4 improves response to anti-PD-1 immunotherapy by reducing Wnt pathway activation and increasing tumor infiltration by T cells.

Iacobuzio-Donahue and colleagues use integrated transcriptomic, histologic and mutational data to analyze squamous features of pancreatic ductal adenocarcinoma (PDAC), further refining the understanding of heterogeneity and evolution in PDAC.

Ajona and colleagues report that short-term starvation synergizes with anti-PD-1 blockade to reduce lung tumor growth and metastasis. This antitumor effect is mediated through the reduction of plasma IGF-1 levels and IGF-1R levels on tumor cells.

Wu et al. develop trispecific antibodies that recognize CD38, CD3 and CD28 and induce T cell activation and co-signaling. They show in mice and non-human primates that by engaging multiple targets, these antibodies induce enhanced tumor-cell killing.

Anagnostou et al. present an improved predictor of response to immune checkpoint blockade that integrates estimates of tumor mutational burden corrected for tumor purity, RTK genomic alterations, a smoking-related mutational signature and HLA status.

Ryan and colleagues analyze genomic features in tumors from African Americans and European Americans and find that homologous recombination deficiency is more prevalent in African Americans.

Martínez-Jiménez et al. report how disruption of the ubiquitin–proteasome system affects cancer, estimating that >10% of driver mutations involve alterations in genes relevant in ubiquitin-mediated proteolysis, including E3 ligases and their targets.