Targeting Systems Vulnerabilities in the EGFR/HER3/HER2 Oncogenic Signaling Circuitry: New Precision Therapies for Oral Cancer

Summary Despite recent advances in treatment, the overall mortality for head and neck squamous cell carcinoma (HNSCC) remains high and current treatment regimens incur significant long-term morbidity. Targeting the immune checkpoint PD-1 with pembrolizumab and nivolumab has revolutionized HNSCC treatment. However, the overall response rate of these immunotherapies remains low, around 15-20%. This highlights the urgent need to identify novel therapeutic options for HNSCC to improve mortality, reduce morbidity, and enhance the activity and response rate of immune oncology (IO) approaches for HNSCC. We hypothesize that targeting HNSCC oncogenic signaling networks and disabling their immune evasive mechanisms may increase the response to anti-PD-1 treatment as part of a novel rational therapeutic strategy. In this regard, our laboratories contributed to the discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that mTOR inhibition exerts potent antitumor activity in multiple experimental HNSCC model systems and in two Phase 2 clinical trial. However, mTORi have shown limited activity in HNSCC in the metastatic, previously treated recurrent, and/or platinum-refractory settings. This highlights the urgent need to identify mechanisms of resistance to mTORi in advanced HNSCC cases, and new options sensitizing to mTORi, without increasing treatment-related toxicities. Our recent findings from multiple systems biology approaches converged to uncover that signaling by the HER receptor family (EGFR, HER2, and HER3) maintains persistent mTOR activation in HNSCC lesions, and that HER receptors blockade prevents mTORi adaptive resistance. We will now aim 1) to exploit synthetic lethal and gene interaction networks to expose druggable systems vulnerabilities upon HER receptors blockade as a precision therapeutic approach for HPV- HNSCC, and 2) to establish the impact of targeting the EGFR/HER3/HER2 (panHER) signaling network in HNSCC on the immune tumor microenvironment and response to ICB. Ultimately, we will exploit the emerging systems level understanding of HER family receptor oncosignaling circuitries in HNSCC for the development of novel rational combinations of targeted and immunotherapies.