Cancer inhibitors shows success in slowing tumour growth
Researchers have successfully demonstrated the potential of using a combination of inhibitors to effectively curb tumour growth and stave off relapses in patients afflicted with specific cancers.
A multinational consortium of researchers has successfully demonstrated the potential of using a combination of inhibitors to effectively curb tumour growth and stave off relapses in patients afflicted with specific cancers, including head and neck squamous cell carcinoma and lung adenocarcinoma. Their discoveries pave the way for the future development of innovative therapeutic strategies aimed at combatting these malignancies. These findings were recently published the journal Oncogene.
Scientific understanding has long held that the Hippo signalling pathway plays a pivotal role in the unchecked proliferation of cancer cells within the human body and in other mammals. At the heart of this process lies the Yes-associated protein 1, or YAP, a critical protein governing the progression of tumour growth, and a key player in the initiation and metastasis of several cancer types. Dysregulation of the Hippo pathway triggers YAP activation, which significantly contributes to the onset of head and neck squamous cell carcinoma. Both the Hippo pathway and YAP have emerged as promising targets for regulating the characteristics of cancer cells.
The Epidermal growth factor receptor, or EGFR, is a cell surface protein with a substantial influence on cell growth. Genetic mutations within the EGFR gene can result in its overactivity, thereby fostering the development of cancer. Notably, in head and neck squamous cell carcinoma, EGFR amplification and high overexpression are common, while in lung adenocarcinoma, EGFR mutations lead to activation. Consequently, EGFR inhibitors, drugs designed to impede cancer growth, are deployed as targeted therapies in combating these specific cancers.
Previous research by the same team unveiled the mechanism by which EGFR activates YAP through the Hippo pathway. However, EGFR-targeted monotherapy has exhibited a low response rate. Based on this evidence, researchers posit that EGFR inhibitors may temporarily deactivate YAP, but when YAP is subsequently reactivated, it fosters resistance to the EGFR inhibitors employed in cancer treatment. The precise mechanisms governing YAP reactivation remain not fully understood.
The current study of the research team focused its attention on AXL, a receptor-type tyrosine kinase. Their objective was to elucidate the mechanism responsible for cancer cells’ resistance to EGFR inhibitors, with a specific emphasis on the novel regulatory role of AXL on YAP. Receptor-type tyrosine kinases, such as AXL, play crucial roles in cellular processes. In its normal state, AXL is predominantly expressed in immune cells, where it participates in the removal of dead cells and the modulation of immune responses. However, when AXL undergoes dysregulation, it can contribute to the development of various cancers, including lung adenocarcinoma, acute leukaemia, and head and neck squamous cell carcinoma.
The research team employed comprehensive transcriptional analysis and conducted in vitro experiments as part of their study. Through these endeavours, the team unveiled that AXL triggers YAP through a novel mechanism when AXL interacts with EGFR. This interaction activates YAP via the EGFR-LATS1/2 axis. LATS1/2, or large tumour suppressor kinases, represent critical members of the Hippo pathway. The researchers determined that the collaborative action of AXL and EGFR inhibitors leads to the inactivation of YAP, ultimately suppressing the viability of cells associated with head and neck squamous cell carcinoma and lung adenocarcinoma.