Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Jan 25:1:603160.
doi: 10.3389/froh.2020.603160. eCollection 2020.

Major Molecular Signaling Pathways in Oral Cancer Associated With Therapeutic Resistance

Saima Usman  1 , Ahmad Jamal  1 , Muy-Teck Teh  1 , Ahmad Waseem  1
Affiliations
Review

Major Molecular Signaling Pathways in Oral Cancer Associated With Therapeutic Resistance

Saima Usman et al. Front Oral Health. .

Abstract

Oral cancer is a sub-category of head and neck cancers that primarily initiates in the oral cavity. The primary treatment option for oral cancer remains surgery but it is associated with massive disfigurement, inability to carry out normal oral functions, psycho-social stress and exhaustive rehabilitation. Other treatment options such as chemotherapy and radiotherapy have their own limitations in terms of toxicity, intolerance and therapeutic resistance. Immunological treatments to enhance the body's ability to recognize cancer tissue as a foreign entity are also being used but they are new and underdeveloped. Although substantial progress has been made in the treatment of oral cancer, its complex heterogeneous nature still needs to be explored, to elucidate the molecular basis for developing resistance to therapeutic agents and how to overcome it, with the aim of improving the chances of patients' survival and their quality of life. This review provides an overview of up-to-date information on the complex role of the major molecules and associated signaling, epigenetic changes, DNA damage repair systems, cancer stem cells and micro RNAs in the development of therapeutic resistance and treatment failure in oral cancer. We have also summarized the current strategies being developed to overcome these therapeutic challenges. This review will help not only researchers but also oral oncologists in the management of the disease and in developing new therapeutic modalities.

Keywords: genetic lesions; head & neck cancers; oncogenic mutations; signaling pathways; therapeutic resistance.

PubMed Disclaimer

Conflict of interest statement

The 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
Factors responsible for therapeutic resistance in oral cancer patients. This review focusses on the complex multiple factors including genetic alterations, dysregulated signaling pathways, EMT/micro RNA and hyperactive DNA damage repair systems. Other factors such as microenvironment (hypoxia), drug metabolism/pharmacokinetics, and immune cells/angiogenesis are also critical in conferring therapeutic resistance in oral cancer, but they have been excluded from this review to maintain the focus.
Figure 2
Figure 2
Strategies to restore p53 functions including growth arrest, induction of apoptosis and senescence during oral cancer treatment. Six different strategies to restore p53 functions discussed in this review are listed here. The proposed reagents employed in every strategy are summarized and discussed in the text.
Figure 3
Figure 3
EGFR signaling pathway (redrawn from [75]). Binding of EGF (and its homologs) to EFGR triggers directly or indirectly cascades of reactions leading to cell survival and cell proliferation. Somatic mutations in EGFR leading to persistent activation is linked to increased growth, reduced apoptosis, increased angiogenesis and metastasis, which are the key features of cancer progression. Two approaches using mAb against EGFR such as cetuximab, and tyrosine kinase inhibitors to suppress anomalous EGFR activation in cancer cells has been shown in the figure.
Figure 4
Figure 4
DNA damage responses and repair pathways (redrawn from [171]). Chemo- and radiotherapy used to treat cancer can cause a variety of damage to the cellular DNA including single-strand break caused by single base damage, crosslinking of bases, mismatch of bases and double strand breaks. This causes hyperactivation of DNA repair machinery which is an important tool utilized by cancer cells to compensate for the damage. Multiple ongoing strategies to block the DNA repair and thus re-sensitize cancer cells to different therapeutic agents are summarized in this figure (red color).
Figure 5
Figure 5
Different mechanisms employed by CSCs for therapeutic resistance (adapted from [184]). CSCs adapt themselves so they can survive the common therapeutic strategies such as chemo- and radiotherapy used to treat oral cancer. These adaptations involve developing mechanisms such as epigenetic modifications, alterations in transport of drug, EMT, stemness, tumor microenvironment, signaling pathways and resistance to apoptosis.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Scully C, Porter S. Oral cancer. West J Med. (2001) 174:348–51. 10.1136/ewjm.174.5.348 - DOI - PMC - PubMed
    1. Rivera C. Essentials of oral cancer. Int J Clin Exp Pathol. (2015) 8:11884–94. - PMC - PubMed
    1. Bagan J, Scully C. Oral cancer: comprehending the condition, causes, controversies, control and consequences. 5. Clinical features and diagnosis of cancer. Dent Update. (2011) 38:209–11. 10.12968/denu.2011.38.3.209 - DOI - PubMed
    1. Gupta N, Gupta R, Acharya AK, Patthi B, Goud V, Reddy S, et al. . Changing Trends in oral cancer - a global scenario. Nepal J Epidemiol. (2016) 6:613–9. 10.3126/nje.v6i4.17255 - DOI - PMC - PubMed
    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. (2011) 61:69–90. 10.3322/caac.20107 - DOI - PubMed

LinkOut - more resources