Targeting TEAD-ious resistance

Abstract

The recent advances in targeting mutant KRAS are limited by resistance. A study in Nature Cancer by Hagenbeek et al. utilizes a novel inhibitor that targets TEAD transcription factors, GNE-7883, to overcome resistance to KRAS inhibitors. Thus, TEAD inhibitors may maximize the durability of KRAS inhibitors in cancer patients.

RAS family GTPases are involved in the mitogen-activated protein kinase (MAPK) pathway signaling, leading to cell proliferation and growth. Mutations in the MAPK pathway have been identified in many cancers, with RAS mutations occurring in about 19% of all cancer patients. The predominant RAS mutations are G12D, G12V, G12C, G13D, and Q61R, which account for 70% of all RAS-mutant cancers. Of all patients with RAS mutations, about 75% occur in KRAS, with KRAS^G12 being the most common mutation in non-small cell lung cancer (NSCLC) [1]. Previously thought to be undruggable, it wasn’t until 2021 that the FDA approved the first drug, sotorasib, that targets KRAS^G12 in NCSLC. A second KRAS inhibitor, adagrasib, has since been FDA approved, while others are currently in ongoing clinical trials (NCT04006301, NCT04956640, NCT04449874). Despite these exciting breakthroughs, both sotorasib and adagrasib have been met with acquired resistance in patients. Studies on resistance mechanisms to KRAS inhibitors are ongoing. A recent clinical study in which 38 tumor samples were analyzed from patients who developed resistance following single-agent therapy of adagrasib. Among those samples, only half were identifiable genetic alterations [2]. These alterations included other KRAS activating mutations and amplifications, mutations in other genes within the RAS pathway, or gene fusions. Further investigation is needed to understand the heterogeneity of acquired resistance mechanisms to KRAS inhibitors to treat these patients more effectively.

Durable response to targeted therapy is limited by tumor plasticity and the survival of drug-tolerant cell subpopulations [3]. Drug-tolerant persisters are cells that survive targeted therapy treatment from which resistant populations can arise. Further understanding of the mechanisms underlying drug tolerance is needed to develop more efficacious targeted therapies and improve the durability of treatment outcomes. In a recent publication in Nature Cancer, Hagenbeek et al. [4] screened over 2 million small molecule inhibitors to find drug candidates that inhibit TEAD activity. The authors found that GNE-7883, an allosteric pan-TEAD inhibitor, reduced cell growth in NF2-deficient mesothelioma lines and several YAP/TAZ-TEAD dependent cancer cell lines (breast cancer, ovarian cancer, and adenocarcinoma). Furthermore, the authors show that GNE-7883 resensitized sotorasib-resistant KRAS mutant NCSLC cell lines to sotorasib (Figure. 1).

Figure 1. Schematic of GNE-7883 functionally reducing adaptive resistance to sotorasib treatment.

A. Sotorasib inhibits the RAS/RAF/MEK/ERK pathway, which decreases cancer cell growth and survival. B. Small populations of cells survive sotorasib treatment, developing resistance and showing elevated levels of YAP/TAZ target gene expression. C. Tumor eventually develops resistance to sotorasib when administered as a monotherapy. However, combination with GNE-7883 inhibits TEAD-driven resistance and results in more effective targeting in mutant KRAS cancer.

The YAP1/TAZ-TEAD signaling pathway plays a critical role in cancer stemness, epithelial-mesenchymal transition, cell proliferation, and survival [5]. When upstream Hippo signaling is turned off, two transcriptional co-activators, YAP1 and TAZ, are unphosphorylated and translocate into the nucleus to interact with TEAD family transcription factors, TEAD1–4. The YAP/TAZ-TEAD pathway can be dysregulated in some cancers via mutations in NF2, which occur in >40% of malignant pleural mesothelioma cases, as well as gene fusions in YAP and/or TAZ [6]. Hagenbeek et al. found that, in several YAP/TAZ-dependent cancer cell lines, GNE-7883 inhibited cell growth in vitro and tumor growth in vivo. ATAC-seq data showed that chromatin accessibility decreased following GNE-7883 treatment around the promotor regions of canonical TEAD targets, ANKRD1 and CYR61, and other YAP signature genes. Furthermore, the authors found that sotorasib-resistant, KRAS mutant G12C cells showed enrichment in YAP/TAZ-TEAD target genes. In both sotorasib- naïve and sotorasib-resistant cell lines, GNE-7883 did not affect NSCLC tumor growth in vivo when used as a single agent; however, GNE-7883 re-sensitized resistant cell lines to sotorasib when administered as a combination therapy.

The development of GNE-7883 adds to the growing area of research into TEAD inhibitors and their clinical application. There are multiple mechanisms for disrupting TEAD activity. GNE-7883 induces an allosteric shift in all TEAD family members that perturbs TEAD activity, thus, acting as a pan-TEAD inhibitor. Another approach is to block the interactions between YAP1/TAZ and TEAD transcription factors. These interactions occur through 3 interfaces or structural regions of TEAD proteins, with interfaces 2 and 3 representing druggable regions. Additionally, a deep palmitate-binding pocket with a conserved cysteine required for TEAD stability, and subsequent YAP1/TAZ binding, is targetable. MGH-CP1 was the first reported inhibitor of the palmitate-binding pocket [7]. Currently, there are three TEAD inhibitors in ongoing Phase 1 human clinical trials on ClinicalTrials.gov for NF2-deficient mesothelioma: IK-930 from Ikena Oncology (NCT05228015), VT3989 from Vivace Therapeutics (NCT04665206), and IAG933 from Novartis Pharmaceuticals (NCT04857372).

The data presented by Hagenbeek et al. suggest additional uses for TEAD inhibitors. Targeting TEAD activity before tumors reach durable resistance, either through selective pressure or acquired resistance, could benefit patients. Additionally, Hagenbeek et al. show the effectiveness of GNE-7883 in various cancers, highlighting the broad applicability of TEAD inhibitors across multiple cancers. This promising new drug targets TEAD-dependent, drug-persistent tumor cells; however, the need to continue researching YAP/TAZ-TEAD signaling and resistance mechanisms cannot be overlooked.