It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting the BRAF^V600 mutations found in 40–50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited to BRAF^V600 melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAF^V600 melanoma.

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.