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In individuals with specific malignancies, including as head and neck squamous cell carcinoma and lung adenocarcinoma, a combination of inhibitors has been shown to reduce tumour growth and prevent relapse. Their findings encourage the creation of novel therapy modalities that specifically target these tumours in the future.
The findings of the study were published in the journalOncogeneon August 17, 2023. Scientists are aware that the Hippo signalling pathway is crucial to the fast cell proliferation that characterises malignancies in humans and other mammals. Yes-associated protein 1, or YAP, is a protein that is vital in controlling the development of tumours and is crucial to the onset and spread of a number of malignancies. The dysregulation of the Hippo pathway results in the activation of YAP, which aids in the development of head and neck squamous cell carcinoma. Attention has been drawn to the Hippo pathway and YAP as signalling pathways that control the properties of cancer cells. Epidermal growth factor receptor, or EGFR, is a protein in cells that contributes to their growth. When a mutation occurs in the gene for EGFR, it can grow too much, leading to cancer. EGFR is frequently amplified and highly overexpressed in head and neck squamous cell carcinoma, and mutated and activated in lung adenocarcinoma. So the EGFR inhibitor, a drug that blocks the cancers growth, is used as a targeted therapy in fighting these cancers. In earlier work, the research team clarified the mechanism by which EGFR activates YAP through the Hippo pathway. However, EGFR-targeted monotherapy has shown a low response rate. Based on this evidence, researchers believe that EGFR inhibitors may temporarily inactivate YAP, but when YAP is re-activated, it increases resistance to the EGFR inhibitors used to fight the cancer. Scientists do not yet fully understand how the YAP is re-activated. The team focused their current study on AXL, a receptor-type tyrosine kinase. They set out to clarify the mechanism that causes the cancer cells resistance to EGFR inhibitors, specifically focusing on the novel regulatory mechanism of YAP by AXL. Receptor-type tyrosine kinases like AXL play an important role in cell processes. When it is working properly, AXL is mainly expressed in immune cells and does the work of removing dead cells and controlling the duration of immune responses. However, when AXL becomes dysregulated, it can contribute to cancers, including lung adenocarcinoma, acute leukaemia, and head and neck squamous cell carcinoma. The team used comprehensive transcriptional analysis and in vitro experiments in their study. With this research, the team clarified that AXL stimulates YAP through a novel mechanism when AXL combines with EGFR. This combination activates YAP via the EGFR-LATS1/2 axis. LATS1/2, or large tumour suppressor kinases, are important members of the Hippo pathway. The team determined that the combination of AXL and EGFR inhibitors working together inactivates YAP and suppresses the viability of head and neck squamous cell carcinoma and lung adenocarcinoma cells. The combination therapy targeting both EGFR and AXL or YAP simultaneously may effectively suppress tumour growth and prevent resistance and relapse in patients with EGFR-altered cancers, including head and neck squamous cell carcinoma and lung adenocarcinoma, said Toshinori Ando, assistant professor at the Center of Clinical Oral Examination, Hiroshima University Hospital. Looking ahead, the team plans to try to generate effective drugs that can target EGFR, AXL, and YAP. We think that intrinsic YAP activation or acquired re-activation after EGFR-targeted therapy in head and neck squamous cell carcinoma and lung adenocarcinoma has not been clarified yet. We will continue the research, said J Silvio Gutkind, distinguished professor at the Department of Pharmacology, University of California, San Diego. (ANI)
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