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Review
. 2021 Jun 23:2:676643.
doi: 10.3389/froh.2021.676643. eCollection 2021.

Targeting Stress-Response Pathways and Therapeutic Resistance in Head and Neck Cancer

Tasia Bos  1 , J Alex Ratti  1 , Hisashi Harada  1
Affiliations
Review

Targeting Stress-Response Pathways and Therapeutic Resistance in Head and Neck Cancer

Tasia Bos et al. Front Oral Health. .

Abstract

Head and neck cancer is the sixth leading cancer worldwide; head and neck squamous cell carcinoma (HNSCC) accounts for more than 90% of incident cases. In the US, cases of HNSCC associated with human papillomavirus (HPV) have been growing in proportion amongst a younger demographic with superior outcomes to the same treatments, relative to cases associated with tobacco. Yet failures to improve the long-term prognosis of advanced HNSCC over the last three decades persist in part due to intrinsic and acquired mechanisms of resistance. Deregulation of the pathways to respond to stress, such as apoptosis and autophagy, often contributes to drug resistance and tumor progression. Here we review the stress-response pathways in drug response and resistance in HNSCC to explore strategies to overcome these resistance mechanisms. We focus on the mechanisms of resistance to current standard cares, such as chemotherapy (i.e., cisplatin), radiation, and cetuximab. Then, we discuss the strategies to overcome these resistances, including novel combinations and immunotherapy.

Keywords: chemotherapy; head and neck squamous cell carcinoma; oxidative stress; radiotherapy; resistance; targeted therapy.

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Conflict of interest statement

JAR is a part of Light Switch Bio, LLC., a startup company that is developing light-based therapeutics and diagnostics for commercial applications, including the treatment of cancers. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Two strategies to combat therapy-resistance caused by mutant TP53 proteins in HPV(-) HNSCC. Mutant, gain-of-function (GOF) TP53 loses the function of WT TP53 (e.g., cell cycle arrest, DNA repair, apoptosis) and acquires tumor proliferation and metastasis functions (black lines). PRIMA-1 and PRIMA-1-met bind to mutant TP53, interact with the DNA-binding domain, and restore WT TP53 functions (blue lines). Inhibition of HSP90 chaperone machinery destabilizes GOF TP53, which leads to cell death (orange lines).
Figure 2
Figure 2
Small-molecule inhibitors promote cell death in HNSCC cells. (1) In HNSCC cells, anti-apoptotic BCL-2 family proteins are often overexpressed. The BH3-mimetic compound, ABT-263, inhibits the function of these proteins by binding to their hydrophobic pockets. Pro-apoptotic BCL-2 family proteins (BAX, BAK) release to initiate the release of cytochrome c, following downstream caspase cascades that result in apoptosis. (2) Survivin, an Inhibitor of Apoptosis Protein (IAP), inhibits Smac that is released from the mitochondria followed by cell death stimuli. Survivin is also often overexpressed in HNSCC, which can be inhibited by the survivin inhibitor, YM155. (3) Caspase-8, which is activated by extrinsic death receptors (e.g., FAS, TNFR) to induce apoptosis, is mutated and inactivated in ~10% of HNSCC. When caspase-8 is inactivated, RIPK3-mediated necroptosis can be promoted. Necroptosis by radiation is enhanced when combined with a SMAC mimetic, birinapant.
Figure 3
Figure 3
The targets to overcome cetuximab resistance in HNSCC patients. EGFR is overexpressed in most HNSCC, and cetuximab is an FDA approved monoclonal antibody to target EGFR. The HER Family, AXL, and STAT3 are upregulated in cetuximab-resistant HNSCC, and therefore, are targets to overcome cetuximab resistance.
Figure 4
Figure 4
The representative regulatory pathways of cell cycle progression and the mode of action of CDK4/6 inhibitors. Overexpression of Cyclin D1, inactivation of p16INK4A, or inactivated mutations of Rb, which are often observed in HNSCC patients, contribute to uncontrolled cell proliferation. CDK4/6 inhibitors result in the inhibition of E2F transcriptional activity, which show promising prognostic outcomes in HNSCC patients.
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