Combination Therapy as a Promising Way to Fight Oral Cancer

Abstract

Oral cancer is a highly aggressive tumor with invasive properties that can lead to metastasis and high mortality rates. Conventional treatment strategies, such as surgery, chemotherapy, and radiation therapy, alone or in combination, are associated with significant side effects. Currently, combination therapy has become the standard practice for the treatment of locally advanced oral cancer, emerging as an effective approach in improving outcomes. In this review, we present an in-depth analysis of the current advancements in combination therapies for oral cancer. The review explores the current therapeutic options and highlights the limitations of monotherapy approaches. It then focuses on combinatorial approaches that target microtubules, as well as various signaling pathway components implicated in oral cancer progression, namely, DNA repair players, the epidermal growth factor receptor, cyclin-dependent kinases, epigenetic readers, and immune checkpoint proteins. The review discusses the rationale behind combining different agents and examines the preclinical and clinical evidence supporting the effectiveness of these combinations, emphasizing their ability to enhance treatment response and overcome drug resistance. Challenges and limitations associated with combination therapy are discussed, including potential toxicity and the need for personalized treatment approaches. A future perspective is also provided to highlight the existing challenges and possible resolutions toward the clinical translation of current oral cancer therapies.

Keywords: anticancer drugs; combination therapy; oral cancer; signaling pathways; targeted therapy.

Figure 1

DNA-damage-targeting drug mechanisms and possible synergistic co-targeted pathways. DNA-damaging drugs induce cell death signaling. Drugs causing DNA damage combined with TRPV4 agonist, inhibitors of DNA repair mechanisms, inducers of cell death signaling, anti-CD20 mAbs, or inhibitors of PDK, PI3K, MAPK, ERK, EGFR, VEGFR, and CDKIs proteins can enhance antitumoral effects. Abbreviations: 5-FU, 5-fluorouracil; β-AR, β-adrenergic receptor; CDK, cyclin-dependent kinase; CDKIs, CDK inhibitors; cIAP1/2, cellular inhibitor of apoptosis protein 1/2; DPD, dihydropyrimidine dehydrogenase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinases; FdUDP, fluorodeoxyuridine diphosphate; FdUMP, fluorodeoxyuridine monophosphate; FdUR, fluorodeoxyuridine; FdUTP, fluorodeoxyuridine triphosphate; FUDP, fluorouridine diphosphate; FUMP, fluorouridine monophosphate; FUTP, fluorouridine triphosphate; HDAC, histone deacetylase; MAPK, mitogen-activated protein kinases; MEK, MAPK/ERK kinase; NF-κB, nuclear factor κB; PARP1, poly (ADP-ribose) polymerase 1; PDC, pyruvate dehydrogenase complex; PDK, pyruvate dehydrogenase kinase; PTEN, phosphatase and tensin homolog; Rb, retinoblastoma protein; RNA, ribonucleic acid; ROS, reactive oxygen species; TRPV4, transient receptor potential vanilloid 4; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; XIAP, x-linked inhibitor of apoptosis protein. Created by the authors with BioRender.com.

Figure 2

EGFR-targeting drug mechanisms and possible synergistic co-targeted pathways. Inhibition of the EGFR signaling pathways impairs cell proliferation and metastization, and can trigger apoptosis. EGFR inhibitors can be combined with PI3K/AKT, ERK, CDKs, and VEGF inhibitors, radiotherapy, BET inhibitors, Aurora kinase inhibitors, drugs targeting DNA repair pathways, c-Met inhibitors, CTLA-4, SRC, FTPase, NF-κB, IGF1R, and HDAC inhibitors, leading to synergistic effects. Abbreviations: AURKB, aurora kinase B; BRD4 bromodomain-containing protein 4; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EGFR, epidermal growth factor receptor; FTPase, farnesyltransferase; IGF-1R, insulin-like growth factor 1 receptor; Rb, retinoblastoma protein; RTKs, receptor tyrosine kinases; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. Created by the authors with BioRender.com.

Figure 3

Cyclin-dependent kinases and BET inhibition enhancement pathways. Inhibition of the p16-Cyclin D1-CDK4/6-Rb pathway leads to cell cycle arrest and tumor growth suppression. Combining CDKIs with FGFR, EGFR/ERK inhibitors, senolytic drugs, HDAC, BET, or PI3K inhibitors can enhance therapeutic outcomes. Targeting BET proteins hinders cancer development. Combinatorial approaches with BET inhibitors and PI3K inhibitors, drugs targeting proteins involved in transcription or immune checkpoint inhibitors, should improve antitumoral effects. Abbreviations: AP-1, Activator protein 1; AKT, BET, bromodomain and extra-terminal domain; BRD4, bromodomain-containing protein 4; CDK, cyclin-dependent kinase; CDKIs, CDK inhibitors; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinases; E2F, transcription factor; FGFR, fibroblast-growth-factor receptor; G0, Gap 0; G1, Gap 1; HDAC, histone deacetylase; MEK, MAPK/ERK kinase; M, mitosis; mTOR, mammalian target of rapamycin; PD-L1, programmed death-ligand 1; Rb, retinoblastoma protein; RNA pol II; RNA polymerase II; S, synthesis phase; SASP, senescence-associated secretory phenotype. Created by the authors with BioRender.com.

Figure 4

PD-1/PD-L1 targeting and possible synergistic co-targeted pathways. PD-1 and PD-L1 targeting leads to T-cell activation, which increases antitumoral immune responses. To achieve synergistic effects, combinations of PD-1/PD-L1 inhibitors with TLR9 agonists, HDAC inhibitors, BTK, KIR, PDE-5 inhibitors, T4 inhibitors, drugs targeting molecules involved in T-cell activation repression, or drugs targeting pathways and proteins involved in tumor cell growth and survival mechanisms, such as PI3K/AKT, MEK, and STAT3, may be used. Abbreviations: B7-H3, B7 homolog 3 protein; BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; cGMP, cyclic guanosine monophosphate; COX-2, cyclooxygenase-2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GMP, guanosine monophosphate; GTP, guanosine triphosphate; HDAC, histone deacetylase; HLA-C, human leukocyte antigen-C; IDO1, Indoleamine 2,3-Dioxygenase 1; IFN-α, interferon alfa; KIR, killer-cell immunoglobulin-like receptor; MAPK, mitogen-activated protein kinases; MDSC, myeloid-derived suppressor cells; MHC, major histocompatibility complex; NF-κB, nuclear factor κB; NFAT, nuclear factor of activated T cells; NK, natural killer; pDC, plasmacytoid dendritic cell; PDE-5, phosphodiesterase-5; PD-L1, programmed death-ligand 1; PKG, cyclic GMP-dependent protein kinase; Rb, retinoblastoma protein; RTK, receptor tyrosine kinase; T4, thyroxine; TCR, toll-like receptor; TLR9, toll-like receptor 9; Treg, T regulatory cell; VEGFR, vascular endothelial growth factor receptor. Created by the authors with BioRender.com.