MOB3A Bypasses BRAF and RAS Oncogene-Induced Senescence by Engaging the Hippo Pathway

Area of Science:

• Cell Biology
• Cancer Biology
• Molecular Oncology

Background:

• Oncogenic activation of the RTK-RAS-RAF-MEK-ERK pathway is common in human cancers.
• Oncogene-induced senescence (OIS) is a tumor suppressor mechanism that halts cancer cell proliferation.
• The Hippo pathway regulates cell proliferation and is involved in tumor suppression.

Purpose of the Study:

• To identify proteins that can bypass oncogene-induced senescence (OIS).
• To investigate the role of MOB3A in OIS and its potential as a therapeutic target in RAS-pathway driven cancers.

Main Methods:

• Screening of activated kinases and kinase-regulatory proteins.
• Assessing the effect of MOB3A expression on primary cell proliferation under oncogenic signaling.
• Investigating MOB3A's interaction with the Hippo pathway kinases (MST/LATS).
• Evaluating the impact of MOB3 family inhibition on cancer cell proliferation and tumor growth.

Main Results:

• MOB3A expression permits proliferation and suppresses senescence in response to oncogenic RAS and BRAF signals.
• MOB3A and MOB3C uniquely allow primary cell proliferation despite sustained oncogene signaling.
• MOB3A inhibits Hippo/MST/LATS signaling, and its membrane localization mimics OIS bypass seen with elevated YAP.
• Inhibition of MOB3 family members reduces cancer cell proliferation and tumor growth.

Conclusions:

• MOB3A plays a critical role in bypassing oncogene-induced senescence (OIS) by inhibiting the Hippo pathway.
• Targeting MOB3A or YAP/TAZ to re-engage the Hippo pathway presents a potential therapeutic strategy for RAS-pathway driven tumors.