When properly employed, targeted therapies are effective cancer treatments. However, the development of such therapies requires the identification of targetable drivers of cancer development and metastasis. The expression and nuclear localization of the transcriptional coactivators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are increased in many human cancers, and experimental evidence indicates that aberrant YAP or TAZ activation drives tumor formation and metastasis. Although these findings make YAP and TAZ appealing therapeutic targets, both have important functions in adult tissues, so directly targeting them could cause adverse effects. The identification of pathways active in cancer cells and required for YAP/TAZ activity could provide a way to inhibit YAP and TAZ. Here, we show that SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) is an important driver of YAP/TAZ activity in human breast cancer and melanoma cells. SRC activation increased YAP/TAZ activity and the expression of YAP/TAZ-regulated genes. In contrast, SRC inhibition or knockdown repressed both YAP/TAZ activity and the expression of YAP/TAZ-regulated genes. We also show that SRC increases the activity of YAP and TAZ by repressing large tumor suppressor homolog (LATS), and we identify the GTPase-activating protein GIT ArfGAP 1 (GIT1) as an SRC effector that regulates both YAP and TAZ. Importantly, we demonstrate that SRC-mediated YAP/TAZ activity promotes tumor growth and enhances metastasis and that SRC-dependent tumor progression depends, at least in part, on YAP and TAZ. Our findings suggest that therapies targeting SRC could help manage some YAP/TAZ-dependent cancers.

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early-phase clinical trials in cancer patients. However, a lack of a reliable way to identify tumors with YAP/TAZ-TEAD activation for most cancer types makes it difficult to determine which tumors will be susceptible to TEAD inhibitors. Here, we used a combination of RNA-seq and bioinformatic analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent in several melanoma cell lines, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. 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.

Background/Objectives: Epithelioid Hemangioendothelioma (EHE) is an ultra-rare, metastatic vascular sarcoma with limited therapeutic options. The hallmark of EHE is a chromosomal translocation that produces the WWTR1-CAMTA1 gene fusion, encoding the aberrant transcriptional regulator TAZ-CAMTA1. Given its central role in the EHE initiation and progression, TAZ-CAMTA1 represents a compelling therapeutic target. Methods and Results: In this study, we identified AMP-activated protein kinase (AMPK) as one of several proteins capable of repressing the TAZ-CAMTA1 transcriptional activity in NIH3T3 and HEK293 cell lines. The pharmacologic activation of AMPK inhibited the proliferation of EHE cell lines without inducing apoptosis; however, in contrast to the NIH3T3 and HEK293 models, AMPK activation in EHE cells unexpectedly increased the TAZ-CAMTA1 expression and activity. Notably, elevated TAZ-CAMTA1 expression was also associated with reduced EHE cell growth, suggesting that the induction of TAZ-CAMTA1 may be one mechanism by which AMPK suppresses EHE growth. Additionally, we found that AMPK inhibits mTOR activity and that direct mTOR inhibition also suppresses EHE cell growth. Conclusions: Together, these findings demonstrate that AMPK activation impairs EHE viability through dual mechanisms: by promoting TAZ-CAMTA1 expression and by inhibiting mTOR signaling. This work highlights AMPK as a potential therapeutic target in EHE and supports the growing body of evidence favoring mTOR inhibitors as promising treatments for this rare cancer.

Epithelioid Hemangioendothelioma (EHE) is an ultra-rare, metastatic vascular sarcoma with limited therapeutic options. The hallmark of EHE is a chromosomal trans-location that produces the WWTR1-CAMTA1 gene fusion, encoding the aberrant transcriptional regulator TAZ-CAMTA1. Given its central role in EHE initiation and progression, TAZ-CAMTA1 represents a compelling therapeutic target. In this study, we identified AMP-activated protein kinase (AMPK) as one of several proteins capable of repressing TAZ-CAMTA1 transcriptional activity in NIH3T3 and HEK293 cell lines. Pharmacologic activation of AMPK inhibited the growth of EHE cell lines; however, in contrast to the NIH3T3 and HEK293 models, AMPK activation in EHE cells unexpectedly increased TAZ-CAMTA1 expression and activity. Notably, elevated TAZ-CAMTA1 expression was also associated with reduced EHE cell growth, suggesting that induction of TAZ-CAMTA1 may be one mechanism by which AMPK sup-presses EHE growth. Additionally, we found that AMPK inhibits mTOR activity, and that direct mTOR inhibition also suppresses EHE cell growth. Together, these findings demonstrate that AMPK activation impairs EHE viability through dual mechanisms: by promoting TAZ-CAMTA1 expression and by inhibiting mTOR signaling. This work highlights AMPK as a potential therapeutic target in EHE and supports the growing body of evidence favoring mTOR inhibitors as promising treatments for this rare cancer.

Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early phase clinical trials in cancer patients. However, mutations that predict YAP/TAZ-TEAD activation are not commonly found in most cancer types, making it hard to determine which tumors are de-pendent upon YAP/TAZ-TEAD. Here, we used a combination of RNA-seq and bioinformatics analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. 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 an effective tool to predict tumor cell sensitivity to YAP/TAZ-TEAD inhibition, and thus provide a means to identify patients likely to benefit from TEAD inhibitors.