In This Issue

CDK4/6 inhibitors (CDK4/6i) are standard of care for treating hormone receptor–positive breast cancer; however, resistance to these drugs is commonly observed. The mechanisms of resistance to CDK4/6i are not well established, hampering development of more effective strategies. Li, Jiang, Guo, and colleagues identified an inducible CDK6–INK4 complex that drives resistance demonstrating that, mechanistically, INK4 blocks the CDK4/6i binding pocket, thereby promoting resistance. Development of a series of CDK4/6 degrader compounds proved effective against CDK6–INK4-expressing, CDK4/6i-resistant breast cancers in vivo, providing impetus for the development of second-generation CDK4/6i.

See article, p. 356.

Standard therapies for advanced aggressive hematologic malignancies, such as leukemias and lymphomas, have a limited effect, with patients experiencing short survival times. Kornauth, Pemovska, Vladimer, and colleagues demonstrated that therapy selection based on results from a functional test is clinically possible and effective in patients with recurrent hematologic cancers. Drug effects on single cells from real-time patient biopsies were quantified using automated high-content microscopy and computerized image analysis, resulting in 54% of patients receiving individually tailored treatment and demonstrating a significant clinical benefit in comparison to their previous therapy. Furthermore, 21% of patients displayed exceptional long-term responses.

See article, p. 372.

Genomic profiling is commonly applied to identify potential treatments for cancer patients. However, only a fraction of patients demonstrate informative mutations, and those who do often do not respond as predicted. Malani and colleagues applied ex vivo sensitivity testing of primary acute myeloid leukemia (AML) cells with hundreds of drugs, along with genomic and transcriptomic profiling. Real-time integration and translation of these data through a functional and molecular tumor board (FMTB) highlighted potential therapeutic options in 97% of patients. Clinical implementation of FMTB recommendations resulted in a 59% objective response rate and the bridging of several patients to hematopoietic stem cell transplantation.

See article, p. 388.

FGFR inhibitors are emerging as promising therapeutic options in cancer but are limited to specific FGFR-aberrant tumors, with acquired resistance being a persistent concern. Meric-Bernstam and colleagues evaluated the irreversible FGFR1–4 inhibitor futibatinib in advanced FGFR-aberrant tumors in a multihistology phase I study of 197 patients. Futibatinib showed clinical activity in a broad range of tumors harboring a variety of FGFR aberrations, with the most robust responses observed in patients with FGFR2 fusion/rearrangement–positive cholangiocarcinoma, including those who progressed on previous FGFR inhibitor therapy. Futibatinib also demonstrated manageable safety. These data form the basis for ongoing phase II/III trials in advanced solid tumors.

See article, p. 402.

Around 25% of diffuse intrinsic pontine gliomas (DIPG) harbor ACVR1 mutations, but currently no specific inhibitors against this receptor are clinically available. Using artificial intelligence to screen approved drugs for potential repurposing, Carvalho and colleagues found vandetanib was able to target mutant ACVR1. When combined with the mTOR inhibitor everolimus, synergy was observed in vitro, central nervous system penetration of vandetanib was improved, and survival was extended in vivo. Furthermore, treatment of four children with ACVR1-mutant DIPG with this combination provided important safety information to inform future clinical trials of these incurable childhood brain tumors.

See article, p. 416.

While large-scale functional genomic screens have revealed hundreds of candidate targets in acute myeloid leukemia (AML), how to prioritize candidates for therapy development remains a challenge. Lin and colleagues established a pipeline for CRISPR screening in orthotopic xenograft models of human AML to nominate AML dependencies with high translational value. Notably, the myo-inositol transporter SLC5A3 was revealed as a metabolic vulnerability for AML cells dependent on extracellular myo-inositol for growth, and MARCH5, a ubiquitin E3 ligase, was identified as a critical apoptosis regulator in AML. Experimental repression of MARCH5 induced apoptosis and enhanced the efficacy of BCL2 inhibitors, such as venetoclax.

See article, p. 432.

Cancer cells are known to have an augmented requirement for extracellular nutrients due to an increased demand for metabolic building blocks to support cell proliferation. Wei and colleagues found that acute myeloid leukemia (AML) cells can acquire a dependency on extracellular inositol, which is mediated by the solute transporter SLC5A3. Unexpectedly, the molecular basis of this nutrient dependency is not because of an elevated demand for inositol in this disease but is due to an acquired defect in inositol biosynthesis that involves the transcriptional silencing of ISYNA1, which encodes for the rate-limiting enzyme of myo-inositol biosynthesis.

See article, p. 450.

Extrachromosomal oncogenic DNA amplifications (ecDNA), which are associated with poor outcomes in cancer, often lack centromeres, resulting in uneven segregation and subsequent rapid ecDNA accumulation and clonal selection of ecDNA-positive cells. Supporting evidence for this phenotype, however, remains incomplete. Yi and colleagues developed the ecTag CRISPR-based method for tagging ecDNAs in live cells, which was used to conclusively demonstrate uneven ecDNA segregation. Applying ecTag to follow ecDNAs after mitosis revealed the nuclear clustering of ecDNAs into ecDNA hubs, which were associated with significantly higher levels of cargo gene transcription, implicating their functional role in activation of cargo oncogenes and tumor proliferation.

See article, p. 468.

The abundant and transcriptionally diverse cancer-associated fibroblast (CAF) population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Helms and colleagues analyzed the differentiation and function of PSCs during tumor progression in vivo and found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and regulation of mechanosignaling.

See article, p. 484.

Therapy resistance is common in glioblastoma (GBM), with GBM stem cells (GSC) playing a major role in this phenotype. Using whole-genome CRISPR screening of patient-derived GSCs, differentiated GBM cells, and neural stem cells, Qiu, Zhao, Shen, and colleagues identified master regulators of GSC stemness. The YY1 and transcriptional CDK9 complex was found to regulate transcription elongation and be necessary for survival and maintenance of GSCs. Genetic or pharmacologic inhibition of this complex elicited interferon responses, reduced regulatory T-cell infiltration, and decreased the efficacy of immune checkpoint blockade therapies.

See article, p. 502.

Many cancers have sex-biased incidence with poorly understood mechanisms. Togami and colleagues investigated BPDCN, an aggressive leukemia of plasmacytoid dendritic cells (pDC) that occurs 3 to 4 times more often in men. Frequent mutations were found in the RNA splicing gene ZRSR2, an X chromosome gene that escapes X inactivation in women, potentially contributing to BPDCN sex bias. A mechanism of pDC transformation associated with aberrant RNA splicing induced by ZRSR2 mutation was explored, which impaired the dendritic cell response to inflammation, interferon production, and apoptosis, thereby revealing a sex- and lineage-related tumor suppressor pathway within this disease.

See article, p. 522.

Metastasis is responsible for most cancer deaths, and yet the genetic or genomic contributions to the metastatic state are poorly understood. Maddipati, Norgard, Baslan, and colleagues used mouse modeling and human data to identify molecular differences between tumors with divergent metastatic properties. Highly metastatic tumors were enriched for focal amplifications and copy-number gains in the MYC oncogene and/or upregulation of MYC target genes. MYC stimulated metastasis by recruiting proinvasive macrophages, leading to an increase in tumor cell intravasation. These results establish MYC as a critical determinant of metastatic burden that is activated by copy-number alterations rather than point mutations.

See article, p. 542.

Loss-of-function alterations in SMARCA4, a gene encoding for a catalytic subunit of SWI/SNF chromatin remodeling complexes, frequently occur in human lung adenocarcinoma (LUAD). However, the precise tumor-suppressive functions of Smarca4 in the lung have been unclear to date. Concepcion and colleagues identified the cell of origin as a critical determinant of Smarca4-mediated tumor suppression in the lung and show that CCSP⁺ cells are sensitive to malignant transformation and rapid tumor progression in the absence of SMARCA4. Further, SMARCA4 inactivation impairs the ability of SWI/SNF complexes to bind and open chromatin, resulting in decreased chromatin accessibility at lung lineage motifs and leading to poorly differentiated tumors and increased metastatic incidence.

See article, p. 562.