Pharmacological inhibition of MYC to mitigate chemoresistance in preclinical models of squamous cell carcinoma

Abstract

Rationale: Cisplatin-based chemotherapy is the first-line treatment for late-stage head and neck squamous cell carcinoma (HNSCC). However, resistance to cisplatin has become a major obstacle for effective therapy. Cancer stem cells (CSCs) are critical for tumor initiation, growth, metastasis, and chemoresistance. How to effectively eliminate CSCs and overcome chemoresistance remains a key challenge. Herein, we confirmed that MYC plays critical roles in chemoresistance, and explored targeting MYC to overcome cisplatin resistance in preclinical models. Methods: The roles of MYC in HNSCC cisplatin resistance and cancer stemness were tested in vitro and in vivo . The combined therapeutic efficiency of MYC targeting using the small molecule MYC inhibitor MYCi975 and cisplatin was assessed in a 4‑nitroquinoline 1-oxide-induced model and in a patient-derived xenograft model. Results: MYC was highly-expressed in cisplatin-resistant HNSCC. Targeting MYC using MYCi975 eliminated CSCs, prevented metastasis, and overcame cisplatin resistance. MYCi975 also induced tumor cell-intrinsic immune responses, and promoted CD8 + T cell infiltration. Mechanistically, MYCi975 induced the DNA damage response and activated the cGAS-STING-IRF3 signaling pathway to increase CD8 + T cell-recruiting chemokines. Conclusions: Our findings suggested that targeting MYC might eliminate CSCs, prevent metastasis, and activate antitumor immunity to overcome cisplatin resistance in HNSCC.

Decoding the research landscape of drug resistance and therapeutic approaches in head and neck cancer: a bibliometric analysis from 2000 to 2023

“…Drugadjuvant therapies such as chemotherapy and immunotherapy play a key role in the treatment of head and neck cancer, improving surgical outcomes and reducing recurrence risk. (Harrington et al, 2023;Liu et al, 2024a). However, drug resistance during treatment limits long-term efficacy.…”

“…It has potential efficacy against drug-resistant head and neck cancer by inhibiting cancer cell proliferation and promoting apoptosis (Guo et al, 2019;Gao et al, 2020). In addition, artemisinin (Li, 2021) and its derivatives are complementary in traditional Chinese medicine (Roh et al, 2017). Studies have shown that they can regulate tumor cell signaling through multiple pathways and inhibit drug resistance in head and neck cancer.…”