The Prognostic and Therapeutic Potential of DNA Damage Repair Pathway Alterations and Homologous Recombination Deficiency in Lung Cancer

Abstract

Lung cancer remains the second most commonly diagnosed cancer worldwide and the leading cause of cancer-related mortality. The mapping of genomic alterations and their role in lung-cancer progression has been followed by the development of new therapeutic options. Several novel drugs, such as targeted therapy and immunotherapy, have significantly improved outcomes. However, many patients with lung cancer do not benefit from existing therapies or develop progressive disease, leading to increased morbidity and mortality despite initial responses to treatment. Alterations in DNA-damage repair (DDR) genes represent a cancer hallmark that impairs a cell’s ability to prevent deleterious mutation accumulation and repair. These alterations have recently emerged as a therapeutic target in breast, ovarian, prostate, and pancreatic cancers. The role of DDR alterations remains largely unknown in lung cancer. Nevertheless, recent research efforts have highlighted a potential role of some DDR alterations as predictive biomarkers of response to treatment. Despite the failure of PARP inhibitors (main class of DDR targeting agents) to improve outcomes in lung cancer patients, there is some evidence suggesting a role of PARP inhibitors and other DDR targeting agents in benefiting a distinct subset of lung cancer patients. In this review, we will discuss the existing literature on DDR alterations and homologous recombination deficiency (HRD) state as predictive biomarkers and therapeutic targets in both non-small cell lung and small cell lung cancer.

New Approaches in Early-Stage NSCL Management: Potential Use of PARP Inhibitors and Immunotherapy Combination

“…This genetic stability is maintained through several cellular mechanisms such as regulation of DNA damage signaling, recruiting effector proteins for DNA repair, chromatin remodeling, transcription, and stabilization of replication forks. The actual impact of DNA-damage repair (DDR) gene alterations remain unsatisfactorily explored in oncology, and research concerning its role in the genesis and progression of cancer, and potential therapeutic targets is ongoing, including in lung cancer [ 63 , 64 , 65 , 66 ].…”

“…Smoking is a major risk factor in lung cancer, it induces DNA damage, and promotes the activation of several repair mechanisms that might offer a rationale for targeting DDR defects in selected lung cancer patients. Even though smoking-related lung cancer is related to a higher tumor mutational burden (TMB), it remains uncertain if specific DDR gene alterations are more common in lung cancer that arises in smokers [ 66 , 67 ].…”

“…These findings explain, at least partially, the reason why alterations in DDR genes are identified in 1/3 of malignancies and raise several questions regarding the role of such deficiencies in lung cancer [ 65 , 66 , 68 ]. Some series report that the overall frequency of HRR mutations in NSCLC is about 14.2%, the most common mutated genes being ATM, BRCA2, AT-rich interactive domain-containing protein (ARID) 1, CHEK2, BRCA1, ATR, RAD50, MSI, and also high TMB.…”

“…Patients with NSCLC that are DDR mutants are associated with better clinical outcomes when treated with PD-(L)1 blockade, as DDR gene alterations correlate with an increase in tumor-infiltrating lymphocytes, genomic instability, TMB, and PD-L1 expression [ 67 , 72 ]. The existence of defective DDR pathways leads cancer cells to rely on other compensatory DDR mechanisms that could also be further explored as a therapeutic target [ 66 ].…”

“…Lastly, it PARylates itself (auto-PARylation) resulting in the release of PARP from the DNA and allowing DNA-repairing proteins to access DNA and terminate the repair process [ 65 , 68 ]. This fact is of extreme importance, as several drugs that target DDR alterations are already approved in some specific settings and new others are under development [ 66 ].…”