In This Issue

Differential somatic mutation patterns between race/ethnicity and sex in early-onset colorectal cancer (CRC) have not yet been fully elucidated. Holowatyj and colleagues evaluated 6,903 patients with CRC along with clinical-grade targeted sequencing data from AACR Project GENIE and found that non-Hispanic Black, but not Asian/Pacific, patients with early-onset nonhypermutated tumors had higher adjusted tumor mutation rates compared with non-Hispanic white patients. Differences in FLT4, FBXW7, RNF43, LRP1B, APC, PIK3CA, and ATRX mutation rates between racial/ethnic groups and EP300, KRAS, AXIN2, WRN, BRAF, and LRP1B mutation rates by sex were observed in nonhypermutated early-onset CRC. Overall, these findings provide novel molecular insights into the biology underpinning early-onset CRC disparities.

See article, p. 570.

To address the issue of antigen escape, Larson and colleagues used T cells enriched for naive and memory phenotypes (T_N/MEM cells) and engineered to express a bispecific chimeric antigen receptor (CAR) targeting CD19 and CD20 to treat patients with relapsed and refractory non-Hodgkin lymphoma. Results from 10 patients in this phase I trial showed a 90% overall response rate and a 70% complete response rate, with median progression-free survival of 18.2 months. No patient experienced neurotoxicity, and the maximum cytokine release syndrome observed was grade 1. These results underscore the potential of bispecific CD19/CD20 CAR-T_N/MEM cells to increase antitumor efficacy and durability while maintaining a robust safety profile.

See article, p. 580.

Fusions of ROS1 tyrosine kinase drive non–small cell lung and other cancers. In this study, Drilon, Horan, Tangpeerachaikul, and colleagues present data on the macrocycle NVL-520, which was designed to address the limitations of earlier generation inhibitors. In preclinical experiments, NVL-520 inhibited ROS1 and ROS1 secondary resistance mutations, exhibited brain penetration, and spared TRKB inhibition, which has been linked to neurologic toxicities. As clinical proof of concept, NVL-520 demonstrated antitumor activity in patient case studies of ROS1 inhibitor–refractory lung cancers, including two with the ROS1 G2032R resistance mutation and one with intracranial metastases, with no observed neurologic toxicities.

See article, p. 598.

Despite the increasing prevalence of liver cancer worldwide, current detection methods are insufficient. In this study, Foda, Annapragada, and colleagues used genome-wide cell-free DNA (cfDNA) fragmentome analyses to evaluate individuals with hepatocellular carcinoma (HCC) or those who were at average or high risk for developing HCC. A machine learning model that incorporated multifeature fragmentome data detected cancer with high sensitivity and specificity, even at its earliest stage. These results were validated in an independent population. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection.

See article, p. 616.

Treatment resistance in advanced prostate cancer can emerge due to transdifferentiation from adenocarcinoma into aggressive neuroendocrine prostate cancer (NEPC). Thus, distinguishing cancer phenotypes has clinical relevance for therapy selection and treatment response, but the need for a biopsy to diagnose tumor histology can be challenging. De Sarkar, Patton, and colleagues characterized the gene regulation of prostate cancer phenotypes using circulating tumor DNA (ctDNA) isolated from patient-derived xenografts. Informed by these results, computational models capturing inferred nucleosome features from ctDNA were developed to accurately classify NEPC from patient plasma, including for mixed phenotypes, demonstrating the potential for noninvasive applications in precision oncology.

See article, p. 632.

Neurofibromatosis type 1 (NF1) is a common inherited tumor predisposition syndrome, and malignant peripheral nerve sheath tumors (MPNST) affect 10% to 15% of people with NF1, resulting in high morbidity and mortality. Cortes-Ciriano and colleagues describe the complex genomic landscape of MPNSTs and found genomic patterns of tumor evolution marked by differing methylation status. These differing molecular profiles correlated with prognosis and were detectable in cell-free DNA. The results can inform both preclinical therapeutic studies and efforts at earlier detection through liquid biopsy surveillance of people with NF1 known to be at risk of MPNST.

See article, p. 654.

Drugs that target two or more pathways provide greater clinical benefit, with bipotent drugs having decreased risk of adverse events. However, identification of bipotent gene targets has not been fully realized due to a lack of systematic approaches. Sahu, Wang, Munson, and colleagues present BipotentR, which identifies drug targets that activate immunity and suppress a second oncogenic pathway. Use of BipotentR led to the identification of 38 new immune–metabolic regulators that can stratify patients based on response to immunotherapy. Moreover, inhibition of the top target, ESRRA, demonstrated tumor killing mediated by suppression of energy metabolism and immune mechanisms.

See article, p. 672.

Somatic and germline mutations of LZTR1, which encodes for a substrate adapter protein of a Cul3 E3 ubiquitin ligase, have been found in numerous cancers and cancer predisposition syndrome. Ko and colleagues characterized the tumor-suppressive mechanism of LZTR1 and showed that LZTR1 induces ubiquitylation-dependent lysosomal degradation of EGFR and AXL, while LZTR1 pathogenic mutants cannot regulate EGFR and AXL cellular balance and lead to dysregulated growth factor signaling. LZTR1-mutant tumors accumulate and activate EGFR and AXL as well as exhibit specific sensitivity to combination treatment with EGFR and AXL inhibitors, suggesting a targeted therapeutic approach for LZTR1-mutated cancers.

See article, p. 702.

Mutations in NPM1 occur in one third of all acute myeloid leukemia and are highly associated with HOXA/B and MEIS1 gene overexpression. However, the mechanisms behind this important association are unknown. Wang, Fan, Han, Liu, and colleagues showed that mutant NPM1 (NPM1c) obtains neomorphic activities of XPO1-dependent chromatin binding and transcription hijacking despite the cytoplasm localization of NPM1c. Unlike transcription factors, NPM1c does not initiate the transcription of HOXA/B and MEIS1 genes, but instead amplifies active transcription. NPM1c also blocks myeloid differentiation by antagonizing histone deacetylase activity. Together, these findings reveal the mechanism of NPM1c's function in regulating HOXA/B genes.

See article, p. 724.

The mechanism of action of mutant NPM1 in acute myeloid leukemia (AML) has primarily been investigated in the context of its aberrant cytoplasmic localization, but it remains unclear if NPM1c directly affects the prominent stem cell–like gene expression pattern observed in human AML samples. Uckelmann and colleagues demonstrated that NPM1c is present in the nucleus, where it plays a direct role in regulating transcription. NPM1c associates with chromatin and cooperates with the histone methyltransferase MLL to enhance transcriptional output. This interplay between NPM1c and the MLL complex on chromatin can be disrupted using Menin–MLL interaction inhibitors, leading to the loss of leukemic self-renewal.

See article, p. 746.

Genomic and microenvironmental aberrations in cancer induce many types of cell stress, which incipient cancer cells must tolerate. Using functional genomic screens of over 1,000 cancer cell lines, Cervia, Shibue, and colleagues identified a ubiquitin ligase complex, the BIRC6 complex, whose role is essential for the survival of a subset of carcinoma cells. Biochemical analyses revealed that the BIRC6 complex enables carcinoma cell survival by preventing the integrated stress response (ISR), highlighting the potential of targeting the stress phenotype of cancer through the inhibition of this ubiquitin ligase complex.

See article, p. 766.