Molecular mechanisms augmenting resistance to current therapies in clinics among cervical cancer patients

Abstract

Cervical cancer (CC) is the fourth leading cause of cancer death (~ 324,000 deaths annually) among women internationally, with 85% of these deaths reported in developing regions, particularly sub-Saharan Africa and Southeast Asia. Human papillomavirus (HPV) is considered the major driver of CC, and with the availability of the prophylactic vaccine, HPV-associated CC is expected to be eliminated soon. However, female patients with advanced-stage cervical cancer demonstrated a high recurrence rate (50-70%) within two years of completing radiochemotherapy. Currently, 90% of failures in chemotherapy are during the invasion and metastasis of cancers related to drug resistance. Although molecular target therapies have shown promising results in the lab, they have had little success in patients due to the tumor heterogeneity fueling resistance to these therapies and bypass the targeted signaling pathway. The last two decades have seen the emergence of immunotherapy, especially immune checkpoint blockade (ICB) therapies, as an effective treatment against metastatic tumors. Unfortunately, only a small subgroup of patients (< 20%) have benefited from this approach, reflecting disease heterogeneity and manifestation with primary or acquired resistance over time. Thus, understanding the mechanisms driving drug resistance in CC could significantly improve the quality of medical care for cancer patients and steer them to accurate, individualized treatment. The rise of artificial intelligence and machine learning has also been a pivotal factor in cancer drug discovery. With the advancement in such technology, cervical cancer screening and diagnosis are expected to become easier. This review will systematically discuss the different tumor-intrinsic and extrinsic mechanisms CC cells to adapt to resist current treatments and scheme novel strategies to overcome cancer drug resistance.

Keywords: Cervical cancer; Drug resistance; Human papillomavirus; Immune checkpoint blockade; Immunotherapy; Metastasis; Recurrence.

Fig. 1

Summary of the main types of therapeutic vaccines used against CC

Fig. 2

The involvement of cellular signaling pathways to CC development or progression. It has been shown that several pathways play important roles in the development or spread of CC. HPV may improve or impair signaling networks' typical operations. In turn, HPV E6 and E7 could activate PI3K/AKT by raising the expression of both PI3K and AKT. By lowering the expression of p53, these HPV oncoproteins prevent the occurrence of apoptotic signaling pathways. Additionally, by increasing the number of EGFRs on the surface of cells infected with HPV, E5 stimulates the PI3K/AKT and MAPK/ERK signaling pathways. It also shows how the loss of antigen presentation will modulate the expression of PDL-1, CD155, CD74, and CD47