Current Landscape of Therapeutic Resistance in Lung Cancer and Promising Strategies to Overcome Resistance

Abstract

Lung cancer is one of the leading causes of cancer-related deaths worldwide with a 5-year survival rate of less than 18%. Current treatment modalities include surgery, chemotherapy, radiation therapy, targeted therapy, and immunotherapy. Despite advances in therapeutic options, resistance to therapy remains a major obstacle to the effectiveness of long-term treatment, eventually leading to therapeutic insensitivity, poor progression-free survival, and disease relapse. Resistance mechanisms stem from genetic mutations and/or epigenetic changes, unregulated drug efflux, tumor hypoxia, alterations in the tumor microenvironment, and several other cellular and molecular alterations. A better understanding of these mechanisms is crucial for targeting factors involved in therapeutic resistance, establishing novel antitumor targets, and developing therapeutic strategies to resensitize cancer cells towards treatment. In this review, we summarize diverse mechanisms driving resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy, and promising strategies to help overcome this therapeutic resistance.

Inhibition of ULK1/2 and KRASG12Ccontrols tumor growth in preclinical models of lung cancer

“…The management of this disease has been transformed by FDA approval of adagrasib and sotorasib, covalent inhibitors of the KRAS G12C oncoprotein [27][28][29] . However, as is generally true for single-agent pathwaytargeted cancer therapy, the emergence of drug resistant disease can be rapid and pleiotropic 50 . Our data suggest that combined inhibition of KRAS G12C plus autophagy may have superior activity against KRAS G12C -driven lung cancer.…”

Activities against Lung Cancer of Biosynthesized Silver Nanoparticles: A Review

“…These adverse effects are manifested due to the poor solubility and lack of tumor specificity of both taxanes [228]. Comparably, first-line chemotherapeutics such as cisplatin and carboplatin have been related to myelosuppression, nephrotoxicity, healthy tissue damage, and neurotoxicity [229]. The adverse effects caused by platinum-based compounds depend upon the dose, individual factors (e.g., age, and diet), and resistance mechanisms [230].…”

“…In LC cells, the presence of such mechanisms can vary in respect to the subtype of LC and the time of clinical presentation. Despite of the tumor heterogeneity among SCLC and NSCLC tumors, drug resistance mechanisms have developed, reducing the efficacy of the current chemotherapeutics (e.g., etoposide, cisplatin, and carboplatin), radiotherapy (e.g., PCI) modalities, immunotherapeutics (e.g., atezolizumab and nivolumab), and targeted therapy (e.g., ALK and EGFR inhibitors) agents [229].…”

Nanomedicine Combats Drug Resistance in Lung Cancer

“…[168] Numerous mechanisms have been reported to contribute to the radioresistance of lung cancer, which include the presence of CSCs, existence of the hypoxic TME, cell cycle redistribution, heightened scavenging of ROS, DNA damage repair, dysregulation of microRNAs, occurrence of EMT, and prevention of apoptosis. [169] Clinical strategies for overcoming radioresistance in lung cancer include: 1) The use of radiosensitizers, such as sodium glycididazole, can effectively boost the sensitivity of hypoxic tumor cells to radiation; [170] 2) The combination of radiotherapy with chemotherapeutic drugs, such as platinum-derived drugs, has been shown to enhance DNA damage and inhibit DNA damage repair, thereby improving the efficacy of radiotherapy; [171] 3) The combination of radiotherapy with molecular targeted drugs, such as EGFR inhibitors, can induce cell cycle arrest and apoptosis, ultimately enhancing the therapeutic effect of radiotherapy; [172] 4) Alteration in the TME through the administration of angiogenesis inhibitors to inhibit angiogenesis and potentiate the effect of radiotherapy. [173] Drug resistance is a great challenge for chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy.…”