Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Abstract

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

The MYC Paralog-PARP1 Axis as a Potential Therapeutic Target in MYC Paralog-Activated Small Cell Lung Cancer

“…Also, c-MYC and MYCN amplification is a predictive biomarker for PARP inhibitor sensitivity in glioblastoma ( 53 ). Most importantly, we and others recently demonstrated that inhibiting RSR pathway is effective in treatment of SCLC ( 54 , 55 ). Together, these studies demonstrated that targeting one or more DDR proteins is a desirable strategy for the treatment of a subset of SCLC.…”

Small-Cell Lung Cancer: Is the Black Box Finally Opening Up?

“…These might be considered as SCLC’s weak spots. After providing a short review on the principles of RS, Bian et al [ 16 ] summarize the source of RS in SCLC and review the strategies to take advantage of this by either increasing the RS or blocking the DDR system in the tumor cells. Of several inhibitors that target the replication stress pathway, PARP1 and WEE1 appear to be the most promising, based both on preclinical and clinical studies.…”

Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer

“…The binding of WEE1 kinases to 14-3-3 protein, which activates WEE1 kinases, may be carried out in two different ways-via the phosphorylation of ser642 (with participation of CHK1) or autophosphorylation. WEE1 inhibitor abrogates the G2/M checkpoint, resulting in cancer cell death coated ssDNA adjacent to the double-stranded DNA (dsDNA) act as a platform to trigger the ATR/CHK1 [35]. ATR combines with ATR-interacting protein (ATRIP), and their complexes are located in the cell nucleus at the sites of DNA damage [36].…”