Matthew Meyerson

Development of KAT6A/B Inhibitors with In Vivo Efficacy

Demonstrates KAT6A/B inhibitor efficacy in vivo, suggesting potential for cancer treatment.

MYC amplification and MYC protein expression are poor prognostic markers in pediatric and young adult osteosarcoma

MYC amplification and high protein expression both independently and concurrently predict poor survival in pediatric and young adult osteosarcoma, beyond metastatic status. Incorporating MYC status into risk stratification may enhance prognostic accuracy and inform targeted therapeutic development.

Mutant p53 protein accumulation is selectively targetable by proximity-inducing drugs

TP53 mutant cancers are associated with approximately half of cancer deaths. The most common mechanism of p53 inactivation involves missense mutations. Such mutations in TP53 result in a robust upregulation of the p53 protein. Here, we demonstrate an induced proximity approach to selectively kill TP53 mutant cells. This approach uses the increased abundance of p53 protein in TP53 mutant cancer cells to concentrate toxic molecules in these cells. We demonstrate this approach with a molecule that binds the Y220C mutant of p53 and concentrates a PLK1 inhibitor in cells harboring TP53 Y220C mutations. The resulting bifunctional molecule promotes formation of a p53 Y220C –PLK1 ternary complex, mislocalizes PLK1, inhibits PLK1 activity, elicits selective G2/M arrest and induces apoptosis in TP53 Y220C cells while sparing wild-type TP53 cells. These data exemplify a potentially generalizable framework for targeting TP53 missense mutations by leveraging mutant p53 protein abundance to induce cell death, independent of p53’s transcriptional activity.

Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer

Preclinical activity of sevabertinib in HER2-mutant lung cancer indicates potential benefit, suggesting new treatment options.

Characterization of tumor-associated microbiome in multifocal small intestinal neuroendocrine tumors (SI-NETs)

Background Small intestinal neuroendocrine tumors (SI-NETs) are among the most common neoplasms of the small bowel; however, the molecular mechanisms underlying their pathogenesis are largely unknown. The multifocal nature of SI-NETs, their putative distinct genomic origins, and their enrichment in the distal ileum led us to hypothesize that environmental factors, such as pathogenic organisms, might play a role in the development of these lesions. Materials and methods To study the tumor-associated microbiome of multifocal SI-NETs and its potential role in pathogenesis, we used matched whole genome and transcriptome sequencing data from a cohort of 10 multifocal SI-NET patients, including 70 primary ileal NETs and their matched normal ileal mucosa and/or whole blood specimens. Results Microbial communities in the ileal tissue samples were primarily composed of bacteria. The most abundant genera included well-known gastrointestinal, oral, and mucosal bacteria. Ileal tissue samples from individual patients contained distinct patient-specific microbial communities. Although the microbiota composition did not show significant differences between ileal NET and normal ileal tissues, genus Propionibacterium was found to be enriched in the normal tissue specimens. Conclusions This study comprehensively characterizes the tissue-resident ileal microbiome of multifocal SI-NET patients. We provide clear evidence that the microbial communities in the ileum are largely patient specific, whereas our genus-level analyses suggest that SI-NET pathogenesis is unlikely driven by individual microorganisms present in the tumors at the time of surgical resection.

Lineage rewiring in lung adenocarcinoma via HNF4α and NKX2-1 dynamics

Experimental models reveal HNF4α's role in lineage plasticity and tumor progression in lung adenocarcinoma, suggesting treatment pathways.

High-Throughput Screening Tool to Identify Small Molecule Inhibitors of Telomerase

High Resolution Image Download MS PowerPoint Slide Telomerase reverse transcriptase is a ribonucleoprotein complex that maintains telomere length in rapidly dividing cells, thus enabling cellular immortality. Despite being recognized as an important cancer target for decades, no small molecule telomerase inhibitors have been approved as anticancer therapeutics to date. Several limitations, including the absence of high-throughput screening tools, have posed challenges to the telomerase drug discovery field. Here, we describe a high-throughput, fluorescently coupled screening methodemploying a chemically modified reporter nucleotide. We utilize the Tribolium castaneum telomerase as a surrogate model as it shares a high degree of active site homology with the human enzyme . We piloted this tool by screening a chemical library of ∼3600 nucleoside mimetics todemonstrate excellent assay quality, and identified 2 compounds with inhibitory activity that were further validated in a direct enzymatic assay. Our work introduces a method that has the potential to uncover novel telomerase inhibitors for further drug discovery efforts.

PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration

The innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in this pathway. We show that PACT directly suppresses PKR activation by endogenous dsRNA ligands, such as inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. Instead of competing for dsRNA binding, PACT prevents PKR from scanning along dsRNA-a necessary step for PKR molecules to encounter and phosphorylate each other for activation. While PKR favors longer dsRNA for increased co-occupancy and scanning-mediated activation, longer dsRNA is also more susceptible to PACT-mediated regulation due to increased PACT-PKR co-occupancy. Unlike viral inhibitors that constitutively suppress PKR, this RNA-dependent mechanism allows PACT to fine-tune PKR activation based on dsRNA length and quantity, ensuring self-tolerance without sequestering most cellular dsRNA.

Discovery and Characterization of BAY-184: A New Potent and Selective Acylsulfonamide-Benzofuran In Vivo-Active KAT6AB Inhibitor

High Resolution Image Download MS PowerPoint Slide KAT6A and KAT6B genes are two closely related lysine acetyltransferases that transfer an acetyl group from acetyl coenzyme A (AcCoA) to lysine residues of target histone substrates, hence playing a key role in chromatin regulation. KAT6A and KAT6B genes are frequently amplified in various cancer types. In breast cancer, the 8p11-p12 amplicon occurs in 12–15% of cases, resulting in elevated copy numbers and expression levels of chromatin modifiers like KAT6A. Here, we report the discovery of a new acylsulfonamide-benzofuran series as a novel structural class for KAT6A/B inhibition. These compounds were identified through high-throughput screening and subsequently optimized using molecular modeling and cocrystal structure determination. The final tool compound, BAY-184 ( 29 ), was successfully validated in an in vivo proof-of-concept study.

PACT prevents aberrant activation of PKR by endogenous dsRNA without sequestration

The innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in the PKR pathway. We demonstrate that PACT is a direct and specific suppressor of PKR against endogenous dsRNA ligands like inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. PACT-mediated inhibition does not involve competition for dsRNA binding. Instead, PACT impairs PKR’s ability to scan along dsRNA––a process necessary for PKR molecules to encounter and autophoshorylate each other for activation. By scanning along dsRNA and directly interacting with PKR, PACT restricts PKR’s movement on dsRNA, reducing the likelihood of PKR molecular collisions and subsequent autophosphorylation, effectively inhibiting PKR without sequestering dsRNA. Consequently, PKR inhibition is more robust with longer and less abundant dsRNA, and minimal with abundant or short dsRNA. Thus, PACT functions to adjust the PKR activation threshold for long endogenous dsRNA without altering its inherent activity, revealing new mechanisms for establishing self-tolerance.

Supplementary Figure S10 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Supplementary Figure S1 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

KRAS WT pancreatic cancer cohort curation and variant filtering

Supplementary Figure S8 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Germline genetic analysis of KRAS WT versus KRAS mutant pancreatic cancer

Supplementary Figure S7 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Copy number gains in MAPK genes are infrequent in KRAS WT, MAPK Negative pancreatic cancer

Supplementary Figure S9 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Dual pan-RAF and MEK inhibition demonstrates synergistic inhibition of pancreatic cancer PDOs harboring BRAF in-frame deletions

Supplementary Figure S7 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Copy number gains in MAPK genes are infrequent in KRAS WT, MAPK Negative pancreatic cancer

Supplementary Figure S4 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

RTK fusions detected in the pancreatic cancer cohort via both DNA-based and RNA-based analyses

Supplementary Figure S10 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Supplementary Figure S3 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Focal chromosomal alterations and oncogenic drivers differ between KRAS WT and mutant pancreatic cancer

Supplementary Figure S2 from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer

Global survey of pancreatic cancer genomics captures known features of disease