Highlighted research articles

Targeted therapy combinations are poised to transform cancer care, but traditional phase I trial designs make exploration difficult in early clinical development. After preclinically demonstrating that the novel SHP2 inhibitor PF-07284892 (ARRY-558) overcomes resistance to diverse targeted therapies, Drilon and colleagues used an alternative dose-escalation design in a phase I trial, allowing for oncogene-matched targeted therapy addition after a SHP2 inhibitor monotherapy lead-in period. In targeted therapy–resistant oncogene-driven cancers treated at dose level one, combination therapy led to rapid tumor and circulating tumor DNA reduction, providing proof of concept for an efficient and patient-centric paradigm for investigating novel–known drug combinations.

See article, p. 1789.

Dysregulation of MDM2 is one mechanism of inactivating wild-type TP53 in cancer and frequently occurs through gene amplifications. Attempts to inhibit MDM2 and indirectly reactivate p53 in clinical trials have been hampered by dose-limiting myelosuppression. In this study, LoRusso and colleagues report on a phase Ib clinical trial in which the MDM2–p53 antagonist brigimadlin (BI 907828) was administered intermittently. This dosing schedule was reported to be tolerable, and preliminary antitumor activity was noted in biliary tract tumors as well as liposarcoma, a disease with pathognomonic MDM2 amplifications.

See article, p. 1802.

Intimal sarcoma is a notably rare, life-threatening malignant neoplasm, and MDM2 amplification is observed in over 70% of intimal sarcomas. Koyama and colleagues conducted a phase Ib/II study of milademetan, an MDM2 inhibitor, in patients with MDM2-amplified, wild-type TP53 intimal sarcoma to evaluate the clinical activity and exploratory resistance mechanism of milademetan. Of the 11 patients enrolled, 10 were included in the efficacy analysis. Two patients (20%) had partial responses and durable antitumor activity for more than 15 months. Acquired TP53 mutations were detected in sequential liquid biopsies as a novel exploratory resistance mechanism to milademetan. Together, these results suggest that milademetan is a potential therapeutic option for intimal sarcoma.

See article, p. 1814.

Patients with germline BRCA–associated pancreatic ductal adenocarcinoma (glBRCA PDAC) are sensitive to platinum/PARP inhibitors, but many develop resistance to these therapies. Stossel, Raitses-Gurevich, and colleagues stratified the spectrum of patient response into three subgroups: refractory [overall survival (OS) <6 months], durable response followed by acquired resistance (OS <36 months), and long-term responders (OS >36 months). These various clinical scenarios were then recapitulated in glBRCA PDAC patient-derived xenografts and ex vivo systems in which comprehensive genomic analyses identified secondary mutations that restore partial functionality and homologous recombination deficiency as major mechanisms of resistance. Together, this work demonstrates the utility of preclinical models in determining resistance mechanisms and aiding future drug development.

See article, p. 1826.

The gastric subtype is the most common variant of intraductal papillary mucinous neoplasms (IPMN) and is typically associated with an indolent biology. Sans and colleagues used region-specific analyses and spatial transcriptomics to show that the expression of the transcription factor NKX6-2 in the epithelium of low-grade IPMNs is associated with a gastric-like transcriptional program and both features are attenuated upon histologic progression. Cross-species validation studies in preclinical models confirmed that NKX6-2 orchestrates a gastric-like differentiation program and IPMN-like glandular morphology, thereby uncovering a previously unknown link between NKX6-2 and the indolent biology of this subtype of pancreatic cystic precursor lesion.

See article, p. 1844.

Constitutive B-cell receptor (BCR) signaling drives diffuse large B-cell lymphomas (DLBCL), but the pathways activated downstream of BCR differ between DLBCL subtypes. Scheich and colleagues sought to identify strategies to target proximal BCR signaling directly and showed that IRF4 expression, which is an indicator of proximal BCR signaling, is reduced upon inactivation of OST-B complex–mediated N-linked protein glycosylation. Moreover, BCR clustering, internalization, and activation of two common downstream BCR signaling molecules, PI3 kinase and NF-κB, are decreased upon inhibition of BCR glycosylation. Additionally, inactivation of OST-B inhibited tumor growth in multiple DLBCL subtypes, suggesting that OST-B inhibitors could be a potential treatment for DLBCL.

See article, p. 1862.

Hürthle cell carcinoma of the thyroid (HTC) is enriched in somatic mitochondrial DNA mutations that impact complex I of the electron transport chain (ETC), but their effects on cellular metabolism are incompletely characterized. Frank and colleagues showed that these mitochondrial DNA–encoded defects in complex I of the mitochondrial ETC in HTC lead to impaired respiration and altered glucose metabolism. In complex I–mutant HTC cells, glycolytic enzymes are essential and small-molecule inhibition of lactate dehydrogenase leads to selective induction of ATP crisis and cell death, suggesting that aerobic fermentation is a therapeutic target in HTC as well as other cancers with genetically encoded ETC defects.

See article, p. 1884.

Previous studies have shown that loss-of-function mutations in complex I genes of the mitochondrial DNA are a defining genetic alteration in oncocytic (Hürthle cell) carcinoma of the thyroid (HCC), but how loss of complex I promotes its tumorigenesis is not yet understood. Gopal, Vantaku, and colleagues sought to systematically define the molecular alterations in HCC as well as identify dependencies in HCC tumors and showed that loss of complex I confers a sensitivity to GPX4 activity loss, which is a critical defense against lipid peroxides and ferroptosis. Moreover, rescue of complex I redox activity diminished sensitivity to ferroptosis, suggesting that lipid peroxide stress is a vulnerability in HCC.

See article, p. 1904.

The pleiotropic mechanisms whereby single cytokines control diverse fate outcomes, including the balance between stemness and differentiation in cancer stem cells, are unknown. Kan, Dhagat, Kaufmann, Hercus, and colleagues employed crystallographic, functional, proteomic, and transcriptomic approaches to show that the structure of the multipotent growth factor IL3 receptor demonstrates two distinct stoichiometric forms, hexamers and dodecamers, and that these are differentially expressed on individual cell types making up the acute myeloid leukemia hierarchy. IL3 receptor hexamers are preferentially expressed on leukemia stem cells, leading to biased activation of signaling and transcriptomic programs that maintain their stemness properties.

See article, p. 1922.