Targeting Nuclear Receptors in Lung Cancer—Novel Therapeutic Prospects

Abstract

Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCON 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.

Liver X Receptors (LXRs) in cancer-an Eagle’s view on molecular insights and therapeutic opportunities

“…RGX-104 was observed to inhibit cellular proliferation, inducing the apoptotic signals, inhibiting MDSCs, and also sensitizing to radiotherapy with reduced immunosuppressive events ( Liang and Shen, 2020 ). Collectively, it was observed that the combination of LXR agonists with other antineoplastic agents has a potent effect against tumor growth and proliferation, and does not have a significant effect when treated alone ( Gangwar et al, 2022 ).…”

Delineating the role of nuclear receptors in colorectal cancer, a focused review

“…Many studies have revealed both tumor-suppressive and oncogenic roles of FXR in CRC [ 35 , 42 , 43 , 100 , 322 ]. The FXR expression increased with the degree of differentiation in HT-29 and Caco2 cells, and it was also demonstrated that the FXR was downregulated in colon carcinomas and adenomas [ 101 ].…”

“…Later, numerous studies stated the critical role of NRs in cancer development and progression [ 38 – 41 ]. Thus, NRs have emerged as novel, highly efficacious therapeutic targets for various malignancies [ 35 , 42 – 44 ]. It has also been observed that nuclear hormone receptors (NHRs) play a crucial role in interacting with hormonal factors in the nucleus and regulation of gene expression [ 36 , 45 ].…”

Exploring the nexus of nuclear receptors in hematological malignancies

“…1 ) [ 38 , 49 ]. An accumulating number of studies have proved the significant role of NRs in the management of different hallmarks of cancers [ 38 , 50 , 51 ]. FDA-approved drugs, like toremifene, raloxifene, and bicalutamide, are designed to target NRs for the treatment of different malignancies [ 52 – 55 ].…”