P53 and Rb Aberrations in Small Cell Lung Cancer (SCLC): From Molecular Mechanisms to Therapeutic Modulation

Abstract

The genes coding for the tumor suppressors p53 and retinoblastoma (Rb) are inactivated in the vast majority of small cell lung cancer (SCLC) tumors. Data support the notion that these two deleterious genetic events represent the initial steps in the development of SCLC, making them essential for a lung epithelial cell to progress toward the acquisition of a malignant phenotype. With the loss of TP53 and RB1, their broad tumor suppressive functions are eliminated and a normal cell is able to proliferate indefinitely, escape entering into cellular senescence, and evade death, no matter the damage it has experienced. Within this setting, lung epithelial cells accumulate further oncogenic mutations and are well on their way to becoming SCLC cells. Understanding the molecular mechanisms of these genetic lesions and their effects within lung epithelial cells is of paramount importance, in order to tackle this aggressive and deadly lung cancer. The present review summarizes the current knowledge on p53 and Rb aberrations, their biological significance, and their prospective therapeutic potential, highlighting completed and ongoing clinical trials with agents that target downstream pathways.

Keywords: Rb; genetic alterations and aberrations; mutations; p53; small cell lung cancer.

Figure 1

The genomic landscape of SCLC. Percentages refer to the frequency of gene mutations. CDKN2A, cyclin-dependent kinase 2A; CREBBP, CREB binding protein; EP300, E1A binding protein p300; FGFR1, fibroblast growth factor receptor 2; IRS2, insulin receptor substrate 2; MYC, v-myc avian myelocytomatosis viral oncogene homolog; MYCL1, v-myc avian myelocytomatosis viral oncogene homolog 1, lung carcinoma derived; MYCN, v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma; RBL1, Rb transcriptional corepressor like 1; RBL2, Rb transcriptional corepressor like 2; TP73, tumor protein 73. This figure was created using tools provided by BioRender.com (accessed on 12 February 2024).

Figure 2

Molecular mechanisms of aberrant p53 and Rb signaling in SCLC. Details are found within the text. The red X sign behind the Rb protein represents Rb inactivation. ATM, ataxia-telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; BAD, BCL2-associated agonist of cell death; CHK1, checkpoint kinase 1; EZH2, enhancer of zeste homolog 2; HDAC, histone deacetylase; PARP1, poly [ADP-ribose] polymerase 1; PUMA, p53 upregulated modulator of apoptosis; Rb, retinoblastoma; RCOR, REST Corepressor; SIRT3, sirtuin-3; SCLC, small cell lung cancer; Ub, ubiquitin; YAP, yes-associated protein. This figure was created using tools provided by BioRender.com (accessed on 12 February 2024).