KRAS G12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.

A noninvasive test for methylated cell-free DNA markers identified colorectal cancer.

Algorithms matching the performance of expert pathologists in prostate cancer diagnosis were designed.

ARID1A is required for response of ER+ breast cancer cells to tamoxifen and fulvestrant but not JQ1.

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity and dismal prognosis. We show that acute activation of Myc in indolent PanIN epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune cell types and trigger transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch.

The St. Jude Cloud, an online resource for cancer researchers to download, upload, process, and visualize pediatric cancer data, has announced the release of the St. Jude Survivorship Portal, which contains a wealth of clinical and genomic data about survivors of childhood cancers.

AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of matched AKT1 E17K-mutant (n=153) and -wildtype (n=302) metastatic breast cancer patients. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wildtype controls (median OS, 24.1 vs 29.9, respectively; p=0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology.

Claudin 6 (CLDN6) may represent a novel target for CAR-T cell therapies aimed at solid tumors.

CD73hi macrophages are enriched in glioblastoma and may contribute to immunotherapy resistance.

Outer radial glia (oRG)–like glioma stem cells (GSC) were enriched in human glioblastomas.

A genome-wide association study identified two risk loci for natural killer T-cell lymphoma (NKTCL).

Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSCs). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem cell self-renewal, which was amplified in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered pro-tumor immunity via transcriptional up-regulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK:BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease.

See article, [p. 40][1] ![][2] Triggering adenosine 2A receptors (A2AR) on the cell surface can suppress the antitumor effects of various immune cells, making A2AR signaling a potentially useful immunotherapy target. Fong and colleagues conducted a phase I clinical trial of the

Summary: In this issue of Cancer Discovery , Fong and colleagues describe the encouraging observations of tumor regression, disease control, and survival of patients with otherwise refractory renal cell cancer with progressive disease after treatment with the conceptually novel oral antagonist of the A2A adenosine receptor (A2AR), ciforadenant. A2AR antagonists may represent the until now missing but critically important part of more effective immunotherapies of cancer, because they prevent the inhibition of tumor-reactive T and natural killer cells by blocking the immunosuppressive hypoxia–A2A–adenosinergic signaling, which represents an emerging immunosuppressive hallmark of tumors that are the most resistant to therapies. See related article by Fong et al., [p. 40][1] . [1]: /lookup/volpage/10/40?iss=1

Summary: Hallin and colleagues demonstrate the preclinical activity of the KRASG12C-specific inhibitor MRTX849 in a series of in vitro and in vivo studies with supporting pilot clinical efficacy. Variable responsiveness despite effective KRASG12C inhibition highlights both the promise and potential need for combinatorial strategies to optimally target KRASG12C-driven cancers. See related article by Hallin et al., [p. 54][1] . [1]: /lookup/volpage/10/54?iss=1

Summary: KRAS G12R mutations occur almost exclusively in pancreatic ductal adenocarcinoma. The results of a study that reveals specific differences in KRAS downstream signaling and metabolic rewiring of pancreatic cancer cells harboring KRAS G12R mutations promise to improve our possibilities to better stratify patients for individualized therapies. See related article by Hobbs et al., [p. 104][1] . [1]: /lookup/volpage/10/104?iss=1

The recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. The cGAS–STING pathway was discovered as an important DNA-sensing machinery in innate immunity and viral defense. Recent advances have now expanded the roles of cGAS–STING to cancer. Highly aggressive, unstable tumors have evolved to co-opt this program to drive tumorigenic behaviors. In this review, we discuss the link between the cGAS–STING DNA-sensing pathway and antitumor immunity as well as cancer progression, genomic instability, the tumor microenvironment, and pharmacologic strategies for cancer therapy. Significance: The cGAS–STING pathway is an evolutionarily conserved defense mechanism against viral infections. Given its role in activating immune surveillance, it has been assumed that this pathway primarily functions as a tumor suppressor. Yet, mounting evidence now suggests that depending on the context, cGAS–STING signaling can also have tumor and metastasis-promoting functions, and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo . In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity. Significance: This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. See related commentary by Sitkovsky, [p. 16][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/10/16?iss=1 [2]: /lookup/volpage/10/1?iss=1

Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line– and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models. Significance: The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents. See related commentary by Klempner and Hata, [p. 20][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/10/20?iss=1 [2]: /lookup/volpage/10/1?iss=1

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN , through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo . Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. Significance: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. Significance: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo –cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

Allele-specific signaling by different KRAS alleles remains poorly understood. The KRAS G12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. Significance: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers. See related commentary by Falcomatà et al., [p. 23][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/10/23?iss=1 [2]: /lookup/volpage/10/1?iss=1

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1 −/− mice, compared with wild-type mice. The antitumor activity observed in Mr1 −/− mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1 −/− mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy. Significance: Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGFβ pathway intact avert this apoptotic effect via ID1. ID1 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGFβ-mediated repression of ID1 . The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA. Significance: Half of PDAs escape TGFβ-induced tumor suppression without inactivating the TGFβ pathway. We report that ID1 expression is selected for in PDAs and that ID1 uncouples TGFβ-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA. This article is highlighted in the In This Issue feature, [p. 1][1] [1]: /lookup/volpage/10/1?iss=1

Michael Birrer, MD, PhD; Levi Garraway, MD, PhD; and Robert Winn, MD, are featured.

Drug shortages in oncology have been an ongoing issue in the United States, leaving clinicians scrambling to ensure that patients have access to therapies. Depleted drug supplies have been particularly acute in pediatric oncology, and a recent shortage of vincristine demonstrates how shortages occur and how treatment centers respond—and highlights the need for better strategies to avoid or mitigate such situations.

Recent results suggest that tucatinib, when combined with trastuzumab and capecitabine, is effective in patients with locally advanced inoperable or metastatic HER2-positive breast cancer who have received prior therapies: In a phase II trial, the drug extended overall survival and progression-free survival compared with trastuzumab and capecitabine alone, and improved progression-free survival in patients with brain metastases.

Siglec-15, which selectively drives immunosuppression in the tumor microenvironment, has emerged as a viable therapeutic target. In a phase I trial of NC318, a Siglec-15 antibody, encouraging efficacy was seen, including a complete response in non–small cell lung cancer refractory to PD-1 blockade.

Preliminary findings suggest that adding bempegaldesleukin to nivolumab may improve responses in patients with metastatic melanoma. In a phase I/II trial, the combination elicited responses in 20 out of 38 patients with newly diagnosed disease and was associated with relatively few side effects.

A new collaboration sponsored by Cancer Research UK will attempt to boost early cancer detection. The partnership involves five institutions in the UK and United States that will to team up to develop and validate new technologies and biomarkers.

A collection of recently published news items.

Clinical trials of two KRASG12C inhibitors, MRTX849 and AMG 510, have shown robust efficacy in phase I trials including patients with non-small cell lung cancer. Data on the effectiveness of the drugs in other tumor types, such as colorectal cancer, have been more limited. Regardless, researchers are excited about the possibility of targeting proteins long thought “undruggable.”

Cancer researchers are heralding the arrival of prime editing, an ultra-precise twist on CRISPR genome engineering, as a powerful new tool for disease modeling, target validation, and clinical applications.

PRIMPOL shields replication forks after multiple rounds of cisplatin in BRCA-deficient cancer cells.

SWI/SNF component SMARCB1's C-terminal domain binds nucleosomes and mediates chromatin remodeling.

In a phase I/II trial, lorlatinib was safe and effective in ROS1 -positive non–small cell lung cancer.

A new MYC inhibitor reduced tumor growth in mouse prostate cancer models.

SD-36, a small-molecule proteolysis-targeting chimera (PROTAC), causes STAT3 degradation in vivo .

Colorectal cancer cells react to targeted therapies by transiently increasing their mutation rate.

An oncogenic superenhancer recruits active MYC to the nuclear pore in colon-cancer cells.

Despite their low mutational burden (TMB), human rhabdoid tumors provoke an immune response.

PD-L1 can repress the CTLA4 axis to stimulate an immune response.

Genomic analysis identified previously unknown potential histiocytosis-driving mutations.

Cis double PIK3CA mutations are common in cancers and increase sensitivity to PI3Kα inhibitors.

The histone acetyltransferase EP300 regulates TCF3–HLF, which promotes acute lymphoblastic leukemia.

In patients with metastatic castration-resistant prostate cancer, pembrolizumab showed efficacy.

Anti-CTLA4 caused Th1 expansion in primary prostate-cancer tumors, but not bone metastases.

Peritumoral expression of Hippo-pathway members YAP and TAZ restricts liver-tumor growth in mice.

Adaptive immunity to commensal viruses reduced the risk of skin cancer in mice.

Phosphorylation of shelterin component TRF2 modulates telomere accessibility across the cell cycle.

The Cancer Discovery editors wish to acknowledge with sincere appreciation the assistance of the following reviewers who have generously contributed their time and effort during the past year[1][1] in the appraisal of manuscripts. These reviewers have been enormously helpful in assessing the merit

A new model for studying T-cell exhaustion in human cells has enabled scientists to discover a transcription factor that, when overexpressed, helps make chimeric antigen receptor T cells resistant to this mechanism of immune failure. A separate team has found that deleting a key phosphatase improved the antitumor function of engineered T cells as well.

BCMA-targeting chimeric antigen receptor T cells increasingly look like a potent option for multiple myeloma. Across several candidates spotlighted during the 2019 American Society of Hematology Annual Meeting, high response rates were seen in patients whose disease was refractory to multiple standard therapies.

Acalabrutinib is a selective irreversible Bruton tyrosine kinase inhibitor that does not affect interleukin-2 associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase 1b/2 study ([NCT02296918][1]) of patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naive and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2-6: 1000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naive) and 92% (relapsed/refractory). Thirty-two percent of treatment-naive and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naive) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naive and relapsed/refractory CLL. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02296918&atom=%2Fcandisc%2Fearly%2F2020%2F01%2F07%2F2159-8290.CD-19-1130.atom

CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-repressor complex. Accordingly, we show that HDAC3 selective inhibitors reverse CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen presentation genes. By reactivating these genes, exposure to HDAC3 inhibitor restored the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence HDAC3 inhibition represents a novel mechanism-based immune-epigenetic therapy for CREBBP mutant lymphomas.

Regulatory T cells (Tregs) are abundant ion human and mouse pancreatic cancer. To understand the contribution to the immunosuppressive microenvironment, we depleted Tregs in a mouse model of pancreatic cancer. Contrary to our expectations, Treg depletion failed to relieve immunosuppression, and led to accelerated tumor progression. We show that Tregs are a key source of TGFβ ligands and, accordingly, their depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts (myCAFs). Conversely, we observed an increase in chemokines Ccl3, Ccl6, and Ccl8 leading to increased myeloid cell recruitment, restoration of immune suppression and promotion of carcinogenesis, an effect that was inhibited by blockade of the common CCL3/6/8 receptor CCR1. Further, Treg depletion unleashed pathological CD4+ Tcell responses. Our data points to new mechanisms regulating fibroblast differentiation in pancreatic cancer and supports the notion that fibroblasts are a heterogeneous population with different and opposing functions in pancreatic carcinogenesis.

Project GENIE, a registry of real-world genomic and clinical cancer data, has announced a 5-year, $36 million collaboration with nine biopharmaceutical companies to obtain detailed information from at least 50,000 patients, which would be added to the 70,000 cases already in Project GENIE's database.

Researchers may finally have identified a first-line treatment for hepatocellular carcinoma that is superior to the current standard. In a phase III trial, atezolizumab plus bevacizumab extended median progression-free survival and overall survival compared with sorafenib, and the combination was associated with a similar rate and severity of side effects as sorafenib.

Four recent studies help explain why extrachromosomal DNA, with its many oncogene amplifications and circular shape, is such a potent driver of tumor growth. The start-up company Boundless Bio aims to apply these insights to the treatment of intractable cancers in which extra loops of DNA are abundant.

A variant of SLC1A5 (SLC1A5_var) fueled pancreatic cancer cells’ mitochondria with glutamine.