Non-small cell lung cancer – mutations, targeted and combination therapy

Abstract

Year after year, a growing number of cases of non-small cell lung cancer (NSCLC), mostly caused by smoking, have been noted. Most patients die because of the late detection of cancer and tumor resistance to treatment with cytostatics. Treatment of patients with advanced NSCLC is impeded by the low sensitivity of the tumor to cytostatic agents and the co-existence of many diseases, which substrate is, like lung cancer, cigarette smoking. Along with the development of molecular biology, targeted therapy has started to be used, affecting specific signaling pathways involved in the processes of oncogenesis. Compounds that inhibit the activity of receptor tyrosine kinases are very well examined and already used in clinical practice. NSCLC is characterized by multiple mutations, including EGFR (epidermal growth factor receptor) and KRAS. Rarer but clinically significant is the rearrangement of the ALK gene. Currently, for NSCLC treatment a number of EGFR inhibitors such as erlotinib, gefitinib, afatinib and two compounds targeted in ALK kinase crizotinib and ceritinib are applied. Unfortunately, despite numerous studies, we are still not able to improve the treatment effectiveness of patients with KRAS mutations. The most efficient solution would be to use a combination of the compounds exhibiting synergistic effects on tumor cells. The literature data describes numerous examples of the combination treatment of NSCLC cells. Some combinations of compounds are already in clinical trials. Most attempts relate to tyrosine kinase inhibitors in combination with other types of pharmacologic inhibitor or immunotherapy. This paper describes the mutations occurring in NSCLC and drugs used in clinical practice as well as being in preclinical development.

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non‐small cell lung cancer cells

“…Lung cancer is the second leading cause of cancer‐related mortality worldwide, and more than 1.6 million cases are diagnosed every year . Tobacco smoking and exposure to environmental carcinogens have been found to be the major risk factors in the development of this disease .…”

“…In this study, we showed that combination therapy with low concentrations of sorafenib and betulinic acid had the capacity to induce high levels of cell death and abolish clonogenic activity in some NSCLC cell lines regardless of KRAS mutations.L ung cancer is the second leading cause of cancer-related mortality worldwide, and more than 1.6 million cases are diagnosed every year. (1,2) Tobacco smoking and exposure to environmental carcinogens have been found to be the major risk factors in the development of this disease. (3) Lung cancer can be classically subdivided into small cell lung cancer (SCLC) and three types of non-small cell lung cancer (NSCLC) that include squamous cell carcinoma, adenocarcinoma and large cell carcinoma.…”

Introductory Chapter: Interactions between Environmental Chemicals and KRAS Oncogene in Different Cancers - Special Focus on Colorectal, Pancreatic, and Lung Cancers

“…Although this treatment method may provide partial or full recovery, it also increases the risk for concurrent diseases. Using anti-cancer drugs with "high efficacy and low-toxicity" is the priority goal in this field [30,31].…”

Diagnostics for Targeted NSCLC Therapy

“…This basic approach is and in future will also be essential to initially define a tumor tissue. Following the microscopic investigation, molecular analyses are requested in order to make therapy decisions, as besides chemotherapeutic regimens also personalized therapies such as tyrosine kinase inhibitors and immunotherapies can be used to treat NSCLC, meanwhile both in first and second line treatments [17][18][19][20][21][22][23]. Thereby it is important to note that, e.g., ALK and PD-L1 immunostainings also belong to the companion diagnostic assays.…”