Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma

Abstract

Lung cancer is the most commonly diagnosed cancer in the world. “Driver” and “passenger” mutations identified in lung cancer indicate that genetics play a major role in the development of the disease, progression, metastasis and response to therapy. Survival rates for lung cancer treatment have remained stagnant at ~15% over the past 40 years in patients with disseminated disease despite advances in surgical techniques, radiotherapy and chemotherapy. Resistance to therapy; either intrinsic or acquired has been a major hindrance to treatment leading to great interest in studies seeking to understand and overcome resistance. Genetic information gained from molecular analyses has been critical in identifying druggable targets and tumor profiles that may be predictors of therapeutic response and mediators of resistance. Mutated or overexpressed epidermal growth factor receptor (EGFR) and translocations in the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) genes (EML4-ALK) are examples of genetic aberrations resulting in targeted therapies for both localized and metastatic disease. Positive clinical responses have been noted in patients harboring these genetic mutations when treated with targeted therapies compared to patients lacking these mutations. Resistance is nonetheless a major factor contributing to the failure of targeted agents and standard cytotoxic agents. In this review, we examine molecular mechanisms that are potential drivers of resistance in non-small cell lung carcinoma, the most frequently diagnosed form of lung cancer. The mechanisms addressed include resistance to molecular targeted therapies as well as conventional chemotherapeutics through the activity of multidrug resistance proteins.

Autophagy is not uniformly cytoprotective: a personalized medicine approach for autophagy inhibition as a therapeutic strategy in non-small cell lung cancer

“…The primary drugs currently used in chemoradiation are the DNA cross linking agents cisplatin and carboplatin, the microtubule poisons paclitaxel and docetaxel and the DNA topoisomerase II inhibitor etoposide 13 . Many of these drugs have significant limitations, including adverse effects, decreased quality of life and drug resistance 14–16 ; consequently, there have been continuing efforts to increase sensitivity of non-small cell lung cancer to these therapeutics.…”

Cbl-b-regulated extracellular signal-regulated kinase signaling is involved in the shikonin-induced apoptosis of lung cancer cells in vitro

“…It accounts for 22% of total cancer mortalities with only a 7% 5-year survival expectancy in the United Kingdom ( 1 ). Non-small cell lung cancer (NSCLC) accounts for ~80% of all diagnosed cases of lung cancer ( 2 ). Chemotherapy plays an important role in the treatment of NSCLC.…”

The small molecule tyrosine kinase inhibitor NVP-BHG712 antagonizes ABCC10-mediated paclitaxel resistance: a preclinical and pharmacokinetic study

“…ABCC10 also mediates the cellular efflux of several other antineoplastic drugs, including docetaxel, vincristine, vinblastine, vinorelbine, cytarabine, gemcitabine, 2′,3′-dideoxycytidine, 9-(2-phosphonyl methoxyethyl)adenine (PMEA), and epothilone B, and endogenous substances such as estradiol-17β-D-glucuronide (E217βG) and leukotriene C4 [ 3 ]. The expression of the ABCC10 transporter is positively correlated with paclitaxel resistance in non-small cell lung cancer (NSCLC) [ 1 , 11 , 12 ]. The ABCC10 transcript is expressed (in order of highest to lowest) in the pancreas, liver, placenta, lungs, kidneys, brain, ovaries, lymph nodes, spleen, heart, leukocytes, and colon [ 13 ].…”