Drug Resistance in Lung Cancer

Lung cancer incidence is very high worldwide and nowadays represents the second most diagnosed cancer and the leading cause of cancer-related death. Treatment options for lung cancer comprise surgical resection, chemotherapy, radiation, targeted therapy, immunotherapy, and/or combinations thereof. The choice of the pharmacological protocol depends on several factors that can accurately categorize patients according to the stage of the cancer, histologic type, tumor size and localization, overall health, and lung function. Patients can be first stratified as surgically resectable or non-resectable based on the pathological diagnosis that highlights the stage/size/metastasis of the tumor according to the TNM guidelines, followed by the identification of specific biomarkers for the tumor microenvironment (TME), such as overexpression of specific proteins (i.e., PD-1/L1) or genes (i.e., EGFR). Almost 30% of lung cancer patients are characterized by genetic alterations and oncogenic driver mutations that actively control tumor cell proliferation and survival. On the other hand, almost 70% of patients do not have gene mutations or alterations; rather, the TME is characterized by infiltrated immune cells which are in their suppressive phenotype, which renders them anergic, therefore uncapable of attacking the tumor mass. Preclinical, clinical, and meta-analyses were used to evaluate the resistance to the current therapy for lung cancer patients. In the attempt to render TME immunologically active, cancer immunotherapy bases its fundamentals on the inhibition of immune checkpoints (ICs), by using monoclonal antibodies (mAbs) that target PD-1, PD-L1, or the cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Ongoing clinical trials are investigating other inhibitors/monoclonal antibodies against ICs, such as lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-3 protein (TIM-3), as well as immune activators (i.e., stimulator of interferon genes, STING, agonist/s). Nevertheless, not all patients respond to the therapy, implying drug resistance. Drug resistance represents the main challenge and the biggest limitation to treat patients with neoplasms. Resistance to cancer therapies can be classified as primary and acquired. Primary resistance is usually defined as intrinsic or innate, it is typical of patient’s phenotype, and it is usually recognized before treatment. Instead, the acquired resistance occurs after pharmacological treatment in patients who are initially sensitive to therapy, but then respond gradually less to the treatment, reducing the effectiveness of the drug. To overcome drug resistance, combination/s of anti-cancer agents represents nowadays a strategy. In this regard, the combination of chemotherapy with immunotherapies or chemotherapy with targeted or gene therapies or targeted therapies with immunotherapies provides the most viable and promising tactic in that it is associated with an increased drug efficacy, reduced therapeutic dose, bypassing severe adverse events, but taking advantage of the synergistic and complementary molecular mechanisms of action. It is clear that the choice of a combination of drugs requires a perfect and profound understanding of the tumor biology in terms of driver molecular pathway/s and/or interaction between the tumor and its microenvironment.