Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Epidermal growth factor receptor (EGFR) is a key driver in many cancers, but EGFR inhibitors (EGFRi) are limited by dose-limiting toxicities and efficacy in specific mutations.
• Current EGFR inhibitor therapy primarily targets kinase activity, leaving potential therapeutic avenues unexplored.

Purpose of the Study:

• To investigate YES1 as a therapeutic target to broaden the efficacy of EGFR inhibitors by reducing EGFR transcription.
• To explore the role of YES1 in regulating EGFR expression in triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC).

Main Methods:

• Investigated the expression of YES1 in TNBC and its effect on EGFR levels.
• Elucidated the signaling pathway through which YES1 influences EGFR expression (YES1 -> JNK -> c-Jun -> EGFR).
• Assessed the synergistic effects of YES1 blockade with EGFR inhibitors in in vitro and in vivo cancer models.

Main Results:

• YES1 is highly expressed in TNBC and promotes cell growth by increasing EGFR levels.
• YES1 signaling via JNK stabilizes the AP-1 transcription factor c-Jun, leading to elevated EGFR expression.
• YES1 sustains EGFR expression in NSCLC, including models with the T790M mutation.
• Combined blockade of YES1 and EGFR inhibitors demonstrated synergistic efficacy in TNBC and NSCLC models, irrespective of EGFR mutations.

Conclusions:

• YES1 plays a critical role in sustaining both wild-type and mutant EGFR expression, presenting a novel therapeutic target.
• Blocking YES1 activity offers a strategy to enhance the efficacy of EGFR inhibitors in a broader range of cancers, including those typically refractory to current treatments.
• Targeting YES1 can lower the threshold for EGFR inhibitor efficacy, expanding treatment options for various EGFR-driven malignancies.