Decades of epidemiological studies demonstrate that smoking-related lung cancer is amongst the most commonly diagnosed cancers in both women and men and that lung cancer incidence is significantly higher in patients who have pre-existing emphysema/lung injury. However, the molecular mechanism(s) linking the two diseases (emphysema and lung cancer) remain unknown, and lung cancer therapy is of limited efficacy in patients with smoking history. This project will provide important data necessary for both development of new therapeutic drugs and generating novel therapeutic regimen to combat smoking-related lung cancer and drug resistance.
To address the pathogenesis of smoking-related lung cancer, the EGF Receptor (EGFR) became our target in the airway epithelium. Our studies clearly established that the EGFR is aberrantly activated during cigarette smoke (CS)-induced oxidative stress in both human airway epithelial (HAE) cells and rodent lungs, leading to cell proliferation. Importantly, many oncologists currently treat lung cancer patients with small molecule tyrosine kinase inhibitors (TKIs), Gefitinib and Erlotinib, which specifically inhibit the EGFR to suppress proliferation of non-small-cell lung cancer (NSCLC) cells. However, we have recently shown that smoking-related resistance to these TKIs could be attributed to post-translational alterations of the EGFR, such as its conformation and interaction with Src kinase (an oncogene activated in CS-exposed lungs). In short, not only CS exposure results in abnormal EGFR activation with prolonged proliferative signaling, but CS-exposed NSCLC cells also become resistant to TKI drugs as observed clinically.
In pursuit of linking smoking-related lung injury to lung cancer, our laboratory identified and continue to study the neutral sphingomyelinase 2 (nSMase2) in the lung, an enzyme that hydrolyzes sphingomyelin to the pro-apoptotic sphingolipid, ceramide. Our studies demonstrate that nSMase2 is specifically activated by CS-induced oxidative stress, generating ceramide and thus leading to apoptosis/cell death, a similar process observed in emphysema patients. Furthermore, we showed that nSMase2 becomes over-expressed in lungs of CS-exposed rodents and of human emphysema patients (smokers).
Based on our recent data, we propose herein that ceramide generation by nSMase2, activated in smoking-induced lung injury, also has a critical, paradigm shifting role in lung cancer development by supporting the aberrant activation of the EGFR in CS-exposed NSCLC, and its interaction with Src. We hypothesize that CS-induced nSMase2 activation and ceramide generation geared towards cellular apoptosis and lung injury are hijacked by cancer cells to promote tumorigenesis. This is an unexpected and unexplored role of nSMase2/ ceramide in lung cancer. We will investigate both in vivo (in mice) and in vitro (in HAE cells) whether nSMase2 over-expression and activation under CS exposure support growth of EGFR-driven lung tumors and their resistance to TKI drugs.
The health system would benefit greatly by investing in these new studies to improve outcomes for US patients, who smoke and thus suffer disproportionally from smoking-related emphysema and lung cancer.
Our new studies, presented in this project, will provide the data needed to develop effective new therapeutic treatments for smoking-related emphysema/COPD and lung cancer diseases, and are therefore of high relevance to TRDRP.