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.

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

“…The dysregulation of tumor suppressor proteins involved in the control of cell proliferation, migration, invasion, and drug response has been established as a key event in cancer origin and progression to aggressive stages. These largely include p53, p21, pRB, p16, p19, PTEN, Keap1, NRF2, PARP1, Her2, and CDKs that have emerged as therapeutic targets in various types of cancers [ 1 , 2 , 3 , 4 ]. Driven by the functional inactivation of a large number of tumor suppressor genes and activation of oncogenes, it involves a complex network of multiple signaling cascades including replication and cell cycle progression, stress and DNA damage response, cell migration, and EMT that are also modulated by intrinsic and extrinsic stresses [ 5 , 6 ].…”