Scientists have uncovered how the interplay between the Hippo signaling pathway and the MAPK pathway contributes to acquired resistance against TEAD inhibitors, shedding light on potential novel therapeutic strategies for treating aggressive cancers such as malignant mesothelioma.
Recent research delves deep beneath the surface of the Hippo pathway, which plays a pivotal role in regulating cell growth and survival. This pathway's dysfunction is often implicated in various cancers, including malignant mesothelioma, where it leads to overactive transcription factors like TEAD. TEADs (Transcriptional Enhanced Associate Domain factors) fortify tumor growth by promoting anti-apoptotic and proliferative signals.
One promising therapeutic strategy employs GNE-7883, a pan-TEAD inhibitor, targeting these transcription factors to mitigate cancer progression. Unfortunately, the study reveals, many cancer cells manage to adapt to this treatment, developing resistance. This emergence of resistance is what this research aims to unravel.
According to the authors of the article, the key mechanism of resistance involves the upregulation of AP-1 transcription factors and the activation of the MAPK pathway, which together restore YAP (Yes-associated protein) and TEAD activity after GNE-7883 disruption. These findings emerged from extensive experiments utilizing various cell line models of malignant mesothelioma.
Researchers conducted dose escalation studies on cancer cells to simulate drug resistance, allowing them to track changes over time. Notably, resistant cells not only restored expression levels of YAP and TEAD but also exhibited heightened chromatin occupancy, allowing easier access and binding to DNA, which is instrumental for the transcription of genes associated with tumor growth.
Further analysis showed increased activity of the MAPK signaling pathway, which appeared to play a compensatory role following TEAD inhibition. These results indicated not just mechanical resilience but also adaptive responses where the cancer cells altered their transcriptional programming to thrive.
One of the standout findings of this research is the pivotal role of the AP-1 family member FOSL1. The study demonstrates how FOSL1 becomes increasingly active in resistant cells and is required for the chromatin binding of YAP and TEAD, thereby maintaining cancer cell survival even amid targeted therapy attempts. This presents FOSL1 as both a marker of resistance and a potential target for future therapies.
The research suggests combining TEAD inhibitors with MAPK pathway inhibitors, like Cobimetinib, could undermine the adaptive responses of resistant tumor cells. This combination strategy was successfully validated through both cell culture and animal models, indicating significant growth suppression. Such evidence gives rise to optimism about enhancing treatment effectiveness and reducing recurrence rates among patients.
Conclusion should suggest follow-ups or clinical trials focusing on combined therapeutic strategies targeting both pathways to not only combat existing resistance but also to create sustainable treatment paradigms for patients grappling with these challenging cancers.