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Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors
Leslie Cuellar-Vite1,2,3, Elyse M Donaubauer1, Kristen L Weber-Bonk2
1Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Abstract:
EGFR is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors (EGFRi) is limited to cancers that harbor sensitizing mutations in the EGFR gene because of dose-limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wild-type (WT) or mutant EGFR. We found that YES1 is highly expressed in triple-negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer cells, including those that harbor the EGFR gatekeeper mutation T790M. The novel ability of YES1 to regulate the expression of WT and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we observed synergy within in vitro and in vivo models of TNBC and non-small cell lung cancer, even in the absence of EGFR-activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by the WT or mutant receptor.
Insights
YES1 elevates epidermal growth factor receptor (EGFR) levels, driving cancer growth. Blocking YES1 enhances EGFR inhibitor efficacy in various cancers, including triple-negative breast cancer and non-small cell lung cancer.
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.
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