Yan-Ting Zhang

Gastroesophageal adenocarcinoma (GEAC) is a significant global cancer burden. Our previous studies demonstrated that YAP/TEAD are highly expressed in GEAC, and play a critical role in tumor progression, therapy resistance, and metastasis. Thus, targeting YAP/TEAD signaling presents a promising therapeutic strategy. Here, we demonstrate that VT00278, a novel compound derived from YAP/TEAD inhibitor CA3, strongly downregulated YAP/TEAD transcriptional activity and potently suppressed tumor-promoting phenotypes including proliferation, invasion and tumor sphere formation. VT00278 induced apoptosis and inhibited tumor growth in vivo especially in radiation-resistant FLO-1 XTR esophageal cancer cells. Mechanistically, in addition to impairing YAP/TEAD signal, VT00278 or YAP depletion repressed RNA polymerase II (RNAPII) transcriptional regulators, reduced RNAPII S2 phosphorylation and decreased anti-apoptotic MCL-1 expression. More interestingly, VT00278 strongly inhibited DNA damage repair, activated cytosolic DNA sensing pathway, and upregulated innate immune genes (e.g., IFNβ). Meanwhile, the upregulation of PD-L1 in VT00278-treated tumor cells possibly contributes to a suppressive immune microenvironment. In a KP-luc2 syngeneic gastric cancer mouse model, combining VT00278 with anti-PD-1 therapy strongly inhibited tumor growth, increased CD3+ and CD8+ T cell infiltration, and induced the production of IFNγ from CD3 and CD8 cells. These findings support that targeting YAP/TEAD with VT00278 as a promising novel therapeutic strategy for GEAC treatment, either alone or in combination with immunotherapy.

Epigenetic dysregulation is a defining feature of solid tumors. Among epigenetic regulators, the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases, comprising NSD1, NSD2, and NSD3, have emerged as critical mediators of oncogenic chromatin remodeling and transcriptional regulation. These enzymes primarily catalyze histone H3 lysine 36 (H3K36) methylation, thereby regulating chromatin accessibility, transcriptional programs, DNA damage repair, and genome stability. Aberrant expression, mutation, amplification, and chromosomal rearrangement of NSD family members have been identified across tumors, establishing them as key epigenetic drivers of malignancy. Accumulating evidence demonstrates that NSD proteins promote multiple hallmarks of cancer, including sustained proliferative signaling, invasion and metastasis, immune evasion, metabolic reprogramming, genome instability, and therapeutic resistance. Although NSD proteins share overlapping catalytic functions, each exhibit distinct biological roles and mechanisms of dysregulation in solid tumors. Advances in structural biology, medicinal chemistry, and targeted protein degradation have accelerated the development of selective NSD inhibitors, chromatin-reader antagonists, and proteolysis-targeting chimeras (PROTACs), establishing the feasibility of pharmacologically targeting NSD-dependent epigenetic pathways. In this review, we summarize the biological functions of the NSD family, discuss their oncogenic mechanisms in solid tumors, and highlight recent progress in therapeutic targeting.

Background: Dysregulation of the Hippo signaling pathway, characterized by aberrant activation of the transcriptional coactivators YAP1 and TAZ, drives tumor progression, immunosuppression, and metastasis. Hippo pathway components are emerging therapeutic targets in several solid tumors, however, the expression profiles of Hippo coactivators YAP1, TAZ, and their transcriptional factors TEAD1-4 in gastric cancer peritoneal metastases (GCPMs), and their therapeutic value, are unknown. In this study, we sought to determine the expression status of YAP1, TAZ, and TEAD1-4 in GCPMs and to evaluate whether dual targeting of YAP1 and TAZ provides superior antitumor activity compared with inhibition of either coactivator alone. Methods: Expression of YAP1, TAZ, and TEAD1–4 was examined in GCPMs by single-cell RNA sequencing and co-immunofluorescent staining. Functional studies using genetic knockout and antisense oligonucleotide (ASO) inhibition of YAP1 or TAZ were performed to assess antineoplastic effects in vitro and in vivo. Co-immunoprecipitation and luciferase reporter assays were used to characterize YAP1/TAZ interactions with TEADs and AP-1 components (JUN and FOSB) and to quantify transcriptional activity. Antitumor efficacy was validated in patient-derived xenograft (PDX) and KP-Luc2 syngeneic models. Results: YAP1, TAZ, and TEADs1-4 were highly coexpressed in GCPMs and correlated with poor survival. YAP1 inhibition alone elicited compensatory upregulation of TAZ, while combined inhibition of both coactivators maximally repressed cell proliferation and invasion in vitro, and tumor growth in vivo. Increased TAZ complexation with TEAD4 and AP-1 (c-JUN and FOSB) heterodimer was observed following YAP1 knockdown or pharmacological ASO inhibition. Dual inhibition of YAP1 and TAZ was required to maximally suppress YAP1/TAZ expression and reduce their nuclear accumulation, transactivation of TEAD, and activation of downstream genes. Conclusions: These findings show that combined YAP1 and TAZ inhibition holds promise for the treatment of GCPM, a highly lethal disease with an urgent need for novel treatment options.

Transcription-associated cyclin-dependent kinases (tCDKs) precisely control the gene transcription process (initiation, elongation, and termination) by mediating RNA polymerase II phosphorylation. In several cancers, disrupted transcriptional control is emerging as a hallmark. In this review we summarize research studies of tCDKs’ role in gastrointestinal (GI) tumors, particularly, in the biology of esophageal, gastric, pancreatic, and hepatobiliary cancers. Across these tumor types, tCDKs are implicated as activators of super enhancer (SE) regions and contribute to the “transcriptional addiction” that not only drives cancer cell growth but is also attributed to therapeutic vulnerabilities. Overall, expression of tCDKs is increased in GI tumor tissues, indicating a rational target for therapeutics. We further describe emerging approaches, including genetic manipulation, small-molecule inhibitors or targeted protein degradation that disrupt tCDK functions in GI malignancies. We conclude by describing key challenges in targeting tCDKs and future treatment directions.

Transcription-associated cyclin-dependent kinases (tCDKs) precisely control the gene transcription process (initiation, elongation, and termination) by mediating RNA polymerase II phosphorylation. In several cancers, disrupted transcriptional control is emerging as a hallmark. In this review we summarize research studies that explored tCDKs’ role in gastrointestinal (GI) tumors, particularly, in the biology of esophageal, gastric, pancreatic and hepatobiliary cancers. Across these tumor types, tCDKs are implicated as activators of super enhancer (SE) regions and contribute to the ‘transcriptional addiction’ that not only drives cancer cell growth but also attribute to therapeutic vulnerabilities. Overall, expression of tCDKs is increased in GI tumor tissues, indicating a rational target for therapeutics. We further describe emerging approaches including genetic manipulation, small-molecule inhibitors or targeted protein degradation that disrupt the functions of tCDK in GI malignancies. We conclude by describing key challenges in targeting tCDKs and future treatment directions.

Background Gastroesophageal cancer (GEAC) remains a major health burden and urgently needs novel therapeutic targets. The inhibition of CDK9’s activity holds the potential to be a highly effective anti-cancer therapeutic. However, the functional role of CDK9, and its potential targeting in GEAC, remain largely unknown. Objective We aim to evaluate the potential of degradation CDK9 in GEAC treatment and explore its mechanisms. Design We evaluated the expression and distribution of CDK9 in GEAC tissue. We designed and synthesized novel CDK9 degraders using proteolysis targeting chimeras (PROTACs) strategy and selected the promising one for further anti-tumor activity evaluation both in vitro and in vivo. We evaluated the effects of CDK9 degradation on epigenetic reactivation, gene expression and chromatin accessibility. We evaluated the co-targeting of CDK9 and YAP/Tead signaling for GEAC treatment, especially for radiation-resistant tumor treatment. Results We demonstrated significantly elevated CDK9 expression in primary GEAC tumor tissues compared to normal tissues, in association with poor survival. We developed a novel CDK9 degrader, YX0597, reducing RNA Pol II Serine 2 phosphorylation, and inhibition MCL-1; this was accompanied by potent inhibition of GEAC cell growth, especially in radiation-resistant tumor cells. Mechanistically, YX0597 strongly enhanced chromatin accessibility, activating epigenetically silenced genes; and dramatically inhibited YAP/TEAD signaling. CDK9 closely interacts with YAP/TEAD signaling, and co-targeting these two mediators could be a novel treatment strategy for the treatment of GEAC. Conclusion Our studies reveal a new avenue for targeting CDK9-hyperactivated GEAC tumors, especially in combination with YAP1/TEAD inhibition in radiation-resistant GEAC tumors. What is already known on this subject?Gastroesophageal cancer (GEAC), the third-leading cause of global cancer death and urgently needs novel targeted therapies. Targeted protein degradation has emerged as an attractive strategy to fight cancer, complementing the activity of traditional small-molecule inhibitors. Cyclin-dependent kinase 9 (CDK9) has been implicated in various cancers. Recently, CDK9 degraders have now been developed for future clinical benefit in targeting tumors with highly activated CDK9. What are the new findings?In this study, we show that CDK9 expression was significantly elevated in primary GEAC tumor tissues including PDXs compared to normal tissues, in association with poor survival. We developed a novel CDK9 degrader XY0597 and proved that it inhibits the progression of GEAC by increasing chromatin accessibility and down-regulating YAP/Tead signaling. We also proved a strong connection between CDK9 and YAP/TEAD signaling and Co-targeting them synergistically inhibits GEAC tumor cell growth, especially in tumors with high YAP signaling activity, such as radiation-resistant cancer. How might it impact on clinical practice in the foreseeable future?Our data suggests that CDK9 is a viable anticancer target in GEAC. We demonstrate that a novel CDK9 degrader, YX0597, has high potential clinical application for GEAC treatment, especially in radiation-resistant cancer. We reveal the crosstalk of CDK9 and YAP/TEAD signaling, and that co-targeting these two mediators could be a new avenue for targeting CDK9-hyperactivated GEAC primary and radiation-resistant tumors.

Within the tumor microenvironment, myeloid cells constitute a dynamic immune population characterized by a heterogeneous phenotype and diverse functional activities. In this review, we consider recent literature shedding light on the increasingly complex biology of M2-like immunosuppressive tumor-associated macrophages (TAMs), including their contribution to tumor cell invasion and metastasis, stromal remodeling (fibrosis and matrix degradation), and immune suppressive functions, in the tumor microenvironment (TME). This review also delves into the intricate signaling mechanisms underlying the polarization of diverse macrophage phenotypes, and their plasticity. We also review the development of promising therapeutic approaches to target these populations in cancers. The expanding knowledge of distinct subsets of immunosuppressive TAMs, and their contributions to tumorigenesis and metastasis, has sparked significant interest among researchers regarding the therapeutic potential of TAM depletion or phenotypic modulation.