Given the limited effectiveness of current treatments, targeting the YAP/TAZ-TEAD signalling cascade has emerged as a promising therapeutic strategy in MPM. Several inhibitors of the YAP/TAZ-TEAD signalling axis are presently undergoing clinical development, with the goal of advancing them to clinical use in the near future.

P1, N=198, Recruiting, Ikena Oncology | Trial completion date: Oct 2024 --> Jun 2025 | Trial primary completion date: Oct 2024 --> Jun 2025

Inhibiting these kinases or the association of YAP/TAZ with PI(4,5)P2 and PI(3,4,5)P3 attenuates YAP/TAZ interaction with the TEADs, the expression of YAP/TAZ target genes, and breast cancer cell motility. Although we could not conclusively exclude the possibility that other enzymatic products of IPMK such as inositol phosphates play a role in the mechanism, our results point to a previously unrecognized role of nuclear phosphoinositide signaling in control of YAP/TAZ activity and implicate this pathway as a potential therapeutic target in YAP/TAZ-driven breast cancer.

Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway.

In addition, activating YAP/TAZ and knocking down the TEAD expression at the same time significant weakened the effect of activated YAP/TAZ signal on precancerous cells and reduced inhibitory effect of knocking down TEAD alone. YAP/TAZ-TEAD signal activates the characteristics and Warburg effect of cancer stem cells, thereby promoting the malignant transformation of CIN.

In the presence of β4, ZEB1 expression is repressed enabling YAP/TAZ/TEAD-mediated transcription of LAMC2. The absence of β4, however, induces ZEB1 and ZEB1 binds to the LAMC2 promoter to inhibit LAMC2 transcription. YAP/TAZ-mediated regulation of LAMC2 has important functional consequences because we provide evidence that LM332 enables carcinoma cells to resist ferroptosis in concert with the β4 integrin.

Importantly, this was not limited to melanoma because this signature was also predictive when tested on a panel of over 1000 cancer cell lines representing numerous distinct cancer types. Our results suggest that YAP/TAZ gene signatures like ours may be effective tools to predict tumor cell dependence upon YAP/TAZ-TEAD, and thus potentially provide a means to identify patients likely to benefit from TEAD inhibitors.

P1, N=156, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2025 --> Oct 2025 | Trial primary completion date: May 2025 --> Oct 2025

P1, N=188, Recruiting, Vivace Therapeutics, Inc | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Feb 2024 --> Nov 2024

P1, N=186, Not yet recruiting, SpringWorks Therapeutics, Inc.

P1, N=82, Recruiting, Betta Pharmaceuticals Co., Ltd. | Not yet recruiting --> Recruiting

HC-258 reduces the CTGF, CYR61, AXL, and NF2 transcript levels and inhibits the migration of MDA-MB-231 breast cancer cells. Co-crystallization with hTEAD2 confirmed that HC-258 binds within TEAD's PA pocket, where it forms a covalent bond with its cysteine.

We focus on several key areas: newly identified molecular patterns of YAP/TAZ activation, emerging mechanisms that contribute to metastasis and cancer therapy resistance, unexpected roles in tumor suppression, and advances in therapeutic strategies targeting this pathway. Moreover, we provide an updated view of YAP/TAZ's biological functions, discuss ongoing controversies, and offer perspectives on specific debated topics in this rapidly evolving field.

Moreover, the combined effect of VT104 and EGFR-TKIs was observed regardless of the localization status of YAP1 before EGFR-TKI exposure. These results suggest that combination therapy with the TEAD inhibitor and EGFR-TKIs may improve the prognosis of patients with EGFR mutation-positive lung cancer.

Accordingly, concurrent treatment with pharmacologic inhibitors of TEAD synergistically enhanced KRASG12C inhibitor anti-tumor activity in vitro and prolonged tumor suppression in vivo. In summary, these observations reveal YAP1/TAZ-TEAD signaling as a crucial driver of primary and acquired resistance to KRAS inhibition and support the use of TEAD inhibitors to enhance the anti-tumor efficacy of KRAS-targeted therapies.

This review highlights the important roles of Yap/Taz in activating Hippo pathway in liver cancer. The recent findings on the crosstalks between the Hippo and other cancer associated pathways and moleculars are also discussed. In this review, we summarized and discussed recent breakthroughs in our understanding of how key components of the Hippo-YAP/TAZ pathway influence the hepatocellular carcinoma, including their effects on tumor occurrence and development, their roles in regulating metastasis, and their function in chemotherapy resistance. Further, the molecular mechanism and roles in regulating cross talk between Hippo-YAP/TAZ pathway and other cancer-associated pathways or oncogenes/cancer suppressor genes were summarized and discussed. More, many other inducers and inhibitors of this signaling cascade and available experimental therapies against the YAP/TAZ/TEAD axis were discussed. Targeting this pathway for cancer therapy may have great significance in the treatment of hepatocellular carcinoma. Graphical summary of the complex role of Hippo-YAP/TAZ signaling in hepatocellular carcinoma.

Our studies identified LM-41 and AF-2112 as two TEAD binders that strongly reduce the expression of CTGF, Cyr61, Axl and NF2. LM-41 gave the strongest reduction of migration of human MDA-MB-231 breast cancer cells.

Importantly, inhibiting the YAP/TAZ-TEAD signaling pathway induces cFLIP down-regulation, leading to a marked sensitization of tumor cells to apoptosis induction by TRAIL. Our data suggest that a combined strategy of targeting TEAD activity and selectively activating apoptosis signaling by agonists of apoptotic TRAIL receptors could be explored as a potential therapeutic approach in cancer treatment.

Finally, SWTX-143 also selectively impaired the growth of NF2-mutant kidney cancer cell lines, suggesting that the sensitivity of mesothelioma models to these YAP/TAZ-TEAD inhibitors can be extended to other tumor types with aberrations in Hippo signaling. In brief, we describe a novel and specific YAP/TAZ-TEAD inhibitor that has potential to treat multiple Hippo-mutant solid tumor types.

To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine-threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components...Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic.

P1, N=156, Recruiting, Novartis Pharmaceuticals | Trial completion date: Sep 2024 --> May 2025 | Trial primary completion date: Sep 2024 --> May 2025

The 44 mesothelioma patients had a median age of 65 (range 21-83), ECOG PS of 0 (n=7) or 1 (n=37), median of 3 prior regimens (range 1-8); all had received prior platinum and pemetrexed, 43/44 (98%) had prior immune checkpoint inhibitors and 16/44 (36%) had VEGF antibodies; 33 had epithelioid, 7 biphasic and 4 sarcomatoid histology. VT3989 is well tolerated with durable responses in patients with refractory mesothelioma. This study provides the first clinical proof-of-concept for drugging the Hippo-YAP-TEAD pathway. RP2D optimization including further schedule evaluation and expansion are ongoing in mesothelioma patients evaluating different intermittent schedules.

Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.

Our study identifies important gene regulatory functions for YAP/TAZ-TEAD-TP63 in the early stages of lung cancer development, which notably includes immune-suppressive roles, and suggest that an assessment of the activity of this transcriptional complex may offer a means to identify immune evasive bronchial PMLs and serve as a potential therapeutic target.

The first FDA-approved KRAS inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRAS mutant NSCLC; however, resistance to therapy is emerging. Mechanistically, the dual inhibition of KRAS and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRAS and TEAD leads to a specific dual cell cycle arrest in KRAS NSCLC cells.

In addition, the bromodomain and extra-terminal domain (BET) inhibitor JQ1 significantly inhibited the transcription of CCBE1, suppressed VEGFC proteolysis and inhibited tumor lymphangiogenesis in vitro and in vivo. Collectively, our study reveals a new positive transcriptional regulatory mechanism of CCBE1 via YAP/TAZ/TEAD4/BRD4 complexes in CRC, which exposes the protumor lymphangiogenic role of YAP/TAZ and the potential inhibitory effect of BET inhibitors on tumor lymphangiogenesis.

In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

P1, N=82, Not yet recruiting, Betta Pharmaceuticals Co., Ltd.

Here we report the identification of IAG933, the first molecule able to potently and directly disrupt the YAP/TAZ-TEADs PPI with suitable properties to enter in clinical trial. Moreover, we provide evidence for combination benefits of IAG933 with several MAPK/KRAS inhibitors, both in vitro and in vivo, in non-Hippo altered models including lung, pancreatic and colorectal cancer. Overall, our results provide a rationale of progressing IAG933 as a monotherapy in patients with Hippo-mutated cancers, and as a combination partner in MAPK-dependent cancers, with the potential to treat patient populations of high unmet medical need.

These results suggest that inhibition of YAP/TAZ-TEAD signaling may improve the efficacy of KRAS-targeted therapy. Taken together, the covalent TEAD inhibitor BGI-9004 has demonstrated promising activity both as a single agent and in combination with other targeted agents, a favorable pharmacokinetic profile and high target selectivity in preclinical models, supporting its evaluation as a novel anti-cancer agent in clinical trials.

Therefore, small molecules that target palmitoylation of TEAD have been explored and VT3989 (NCT04665206) and IK-930 (NCT05228015) have success to enter the clinical trials...In line with the results of the in-vitro experiments, another YAP/TEAD inhibitor TY-0536 in combination with TY-9591 significantly delay the tumor regrowth in the PC9 CDX mouse model...[Shengli Dong and Apeng Liang contributed equally to this work. Jun Li, Shengli Dong, and Apeng Liang are the corresponding authors.]

(iv) favorable ADME profile in rodents, dogs and NHPs, as well as a favorable safety profile. In sum, SPR1 presents monotherapy opportunities in ultra-responder populations based on internal bioinformatic insights, while broader potential exists as an adjuvant for precision oncology targeted therapies, particularly within the MAPK pathway and its upstream activators.

CDKN2A loss enhances the tumorigenicity of EHE in vivo and enabled the generation of. the first cell lines of this disease. These cell line replicate key facets of the human disease phenotype. Therefore, these cell lines and allograft tumors generated after implantation serve as robust model systems for therapeutic testing of compounds either directed at EHE or at other TAZ-driven cancers.

We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.

Further optimization of MYF-03-69 led to an in vivo compatible compound MYF-03-176, which shows strong antitumor efficacy in MPM mouse xenograft model via oral administration. Taken together, we disclosed a story of the development of covalent TEAD inhibitors and its high therapeutic potential for clinic treatment for the cancers that are driven by TEAD-YAP alteration.