Novel Therapeutic Approaches with DNA Damage Response Inhibitors for Melanoma Treatment

Abstract

Targeted therapies against components of the mitogen-activated protein kinase (MAPK) pathway and immunotherapies, which block immune checkpoints, have shown important clinical benefits in melanoma patients. However, most patients develop resistance, with consequent disease relapse. Therefore, there is a need to identify novel therapeutic approaches for patients who are resistant or do not respond to the current targeted and immune therapies. Melanoma is characterized by homologous recombination (HR) and DNA damage response (DDR) gene mutations and by high replicative stress, which increase the endogenous DNA damage, leading to the activation of DDR. In this review, we will discuss the current experimental evidence on how DDR can be exploited therapeutically in melanoma. Specifically, we will focus on PARP, ATM, CHK1, WEE1 and ATR inhibitors, for which preclinical data as single agents, taking advantage of synthetic lethal interactions, and in combination with chemo-targeted-immunotherapy, have been growing in melanoma, encouraging the ongoing clinical trials. The overviewed data are suggestive of considering DDR inhibitors as a valid therapeutic approach, which may positively impact the future of melanoma treatment.

Keywords: ATM; ATR; CHK1; DNA damage response; PARP; WEE1; combined therapy; inhibitors; melanoma.

Figure 1

Schematic representation of the DDR pathway and DDR inhibitors used in preclinical and clinical settings in melanoma. Single strand break (SSB) is recognized by the RPA complex, which leads to the activation of ATR and CHK1. The latter promotes phosphorylation and inactivation of the phosphatases CDC25A and CDC25C, which are involved in dephosphorylation and activation of CDK2 and CDK1, respectively. CHK1 may also be activated by ATM. WEE1 regulates the CDKs activity in a negative manner, playing an essential role in controlling S and M phase entry. The MRN complex recognizes double strand break (DSB), and activates ATM. CHK2 and p53 are the main targets of ATM. Upon activation, CHK2 and p53 can lead to either cell cycle block or apoptosis. Active ATM can also phosphorylate H2AX, which can lead to DNA repair. During SSB formation, ATR can also activate CHK2. PARP, ATR, CHK1, ATM and WEE1 inhibitors are indicated in red. More information about these inhibitors is reported in the main text. DSB can also activate the NHEJ pathway, whose main components include KU70/80, DNA-PK and LIG4/XRCC4. P with red circles stands for phosphorylation.

Figure 2

Schematic representation of the main therapeutic approaches against melanoma. (A) The RAS-RAF-MEK1/2-ERK1/2 pathway is often upregulated in melanoma, with a consequent increase in cell proliferation and survival. Pharmacological inhibition of mutant BRAF or kinase MEK1/2 blocks the MAPK pathway. (B) Activation of T cells requires presentation of the tumor antigen to the T-cell receptor (TCR) through the major histocompatibility complex (MHC) and the interaction of CD28 with B7 ligand, present on the surface of dendritic cells. T cells also express CTLA-4, whose binding to B7 triggers the signal to inactivate T cells. Anti-CTLA-4 antibodies inhibit the interaction between CTLA-4 and B7, leading to T cell activation. (C) Melanoma cells can express high levels of PD-L1, which, through the interaction with the PD-1 receptor on the T cells, causes a reduction in T cell function. Blockade of the PD-L1/PD-1 axis with anti-PD-1 or anti-PD-L1 checkpoint inhibitors restores the ability of T cells to recognize and destroy melanoma cells.

Figure 3

Schematic representation of the therapeutic advantage of using DDR inhibitors in melanoma.