作者: Yang, Bing ; Luo, Ray ; Kizhedathu, Amrutha ; Thilakaratne, Eshan Malinda ; Liu, Yuhan ; Xu, Yun Yi ; Lara-Gonzalez, Pablo ; Wang, Wenqi ; Lin, Tzuling ; Warrior, Rahul ; An, Jeongmin ; Huang, Zhen ; Joo, Hyejin ; Lan, Tian

The Hippo pathway is a key regulator of development, regeneration, tissue homeostasis, and organ size, and its dysregulation promotes tumorigenesis. However, the precise mechanisms of its regulation in both normal physiology and cancer remain incompletely understood. Here, we identify STK38 and STK38L (also known as NDR1 and NDR2), previously proposed as redundant kinases of LATS, as negative regulators of the Hippo pathway. STK38/L inhibit LATS by competitively binding to MOB1 and disrupting the LATS–MOB1 complex, a process independent of their kinase activity. This inhibitory mechanism is evolutionarily conserved, as the Drosophila ortholog Tricornered similarly impairs Warts–Mats complex formation, resulting in enlarged fly wing size. Pathologically, STK38L is highly expressed in ovarian cancer and required for ovarian tumor growth, and its amplification correlates with YAP activation and increased tumor sensitivity to TEAD inhibitors. Taken together, our study reveals a conserved role of STK38/L in Hippo pathway regulation, providing new insights into Hippo-dependent growth control and cancer development.

2026-05-01·Med

Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity

Article

作者: Li, Xiaoyu ; Chintala, Navin K ; Taleb, Meriem ; Lee, Hyun-Sung ; Okada, Tomoyo ; Ningoo, Mehek ; Lopez-Lago, Miguel A ; Burt, Bryan M ; Offin, Michael ; Adusumilli, Prasad S

BACKGROUND:

Investigating the biological mechanisms of acquired resistance to immunotherapy remains a necessity for effective treatment of solid tumors.

METHODS:

Diffuse pleural mesothelioma (DPM) tumors, from immunocompetent and immunodeficient mouse models with acquired resistance to chimeric antigen receptor (CAR) T cell therapy were analyzed using flow cytometry, immunofluorescence, and ELISA. The interplay between genetic alterations in the cancer cell and site-specific tumor immune microenvironment (TIME) was characterized; therapies to reverse immunotherapy resistance were investigated.

FINDINGS:

Analysis of tumors with acquired resistance to CAR T cell therapy demonstrated lower expression of tumor suppressor NF2. Enforced depletion of NF2 promoted resistance to CAR T cell and anti-PD-1 therapy in DPM but not in heterotopic subcutaneous tumors. Loss of NF2 was associated with accumulation of immunosuppressive complement receptor of immunoglobulin superfamily (CRIg)⁺ macrophages in pleural tumors, which was dependent on tumor-secreted chemokines and retinoic acid. Ablation of chemokines or pharmacologic inhibition of retinoic acid or the Hippo pathway by use of TEAD inhibitors restored sensitivity to CAR T cell therapy. Correspondingly, in two independent cohorts of patients, DPM tumors with NF2 copy-number loss, but not mutations, were associated with higher infiltration of M2 macrophages, lower infiltration and function of CD8 T cells, and an anti-PD-1-resistant gene signature.

CONCLUSIONS:

Our study uncovers a previously unknown mechanism of resistance to immunotherapy by identifying the dynamic interplay between cancer cell genetic alterations and the TIME.

FUNDING:

This research was funded in part through the NCI UG3CA290241, R01CA292664, R01CA235667, R01CA236615, and Department of War CA200437.

2026-01-01·microPublication biology

TEAD inhibitors synergize with MEK, SHP2 and mTOR inhibitors in NF1 and NF2 cell lines.

Article

作者: Gurunathan, Sharavana ; Yang, Yang ; Schechter, Shane ; Field, Jeffrey

Neurofibromatosis type 1 (NF1) and NF2 -related Schwannomatosis ( NF2 -SWN) are both inherited syndromes characterized by Schwann cell tumors. NF1 tumors harbor activated Ras/MEK/ERK, while NF2 -SWN tumors harbor activated mechanosignaling pathways, including Hippo/YAP-TAZ/TEAD. To test combinatorial strategies in tumor cell lines, we first screened a new-generation TEAD inhibitor, VT103, against 123 drugs and then validated the hits with pairwise titrations. VT103 consistently synergized with inhibitors of MEK (trametinib and selumetinib), SHP2 (TNO155) and mTOR (everolimus). The highest synergy ZIP score, calculated using SynergyFinder, was ~65 in the NF2 -SWN cell line SC4, with lower magnitudes in an NF1 cell line.

100 项与 TEAD inhibitors(Baobab AiBIO) 相关的药物交易

登录后查看更多信息