It’s been a bit of a long week on lung cancer articles and while I was planning on talking about something else today, this new article in my database caught my eye:
Part of the reason is nostalgia – it’s 20 years ago since I finished my doctorate on early detection of preclinical lung disease and while I was interested in the methods of detecting changes in breathing patterns associated with smoking, part of me wished I’d done research on molecular biology at the time rather than applied physiology.
The reason is that I realised while doing the literature search is that biochemical and physiological changes in the airways would ultimately tell us more about early detection.
In the article above, the researchers suggest a potential mechanism by which the tobacco-specific carcinogen NNK promotes lung tumour formation and development. Now, bearing in mind that most solid tumours take years to develop from hyperplasia to full aggressive carcinoma, finding how it actually happens and why is still an inexact science, as are methods for early detection given not all smokers get lung cancer and non-smokers are not immune from the disease.
Lin et al., suggest that NNK induces the accumulation of a protein known as DNMT1 in the nucleus and that this protein silences genes that suppress tumour formation. They offered evidence to support their hypothesis, including the observation that DNMT1 accumulates in both lung adenomas from NNK-treated mice and tumours from lung cancer patients that were smokers. DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis.
However, the interesting part of their abstract to me was:
“We determined that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated DNMT1 to recruit β-transducin repeat–containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation.”
Ah, our friend AKT.
The potential role of AKT in lung cancer came up repeatedly at last week’s AACR lung cancer meeting. The researchers there had begun to realise that blocking EGFR or IGF-1R and c-MET or AKT (either directly or indirectly via PI3K inhibition) might cut off an escape route for the cancer cell and reduce drug resistance:
Drs Jeffrey Engelman (MGH) and David Carbone (Vanderbilt) covered excellent quick reviews at AACR on the latest findings related to EGFR inhibition relating to c-MET and proteomics respectively. As our knowledge of various mutations and biologic pathways improves, so does our understanding of how we can better target aberrations and treat patients with NSCLC more effectively.
Engelman’s group has just published a paper on c-MET and EGFR inhibition (see references). They noticed that rare MET-amplified cells exist in some EGFR-mutant lung cancers before treatment. What makes the research relevant to this overview is that MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. They demonstrated that MET activation by its ligand, HGF, induces drug resistance through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, they identified subpopulations of cells with MET amplification prior to drug exposure.
The concept that HGF induces resistance to tyrosine kinase inhibitors in EGFR-addicted cancers is a novel one. They saw that HGF accelerates MET amplification by expanding preexisting MET-amplified cells. What was particularly relevant though was that analysis of pretreatment cancers identified those poised to become MET amplified, thereby offering a way to segment NSCLC patients for more personalised treatment, increasing the chances of better response rates, longer overall survival and improved patient outcomes.
Then came the killer statement:
“EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition.”
Oh my. This leaves us seriously wondering what will happen in practice by combining erlotinib (Tarceva) or gefitinib (Iressa) with a MET inhibitor in patients with NSCLC? Tang et al., reported some promising preclinical work in 2008 (see references) but solid data in human patients has yet to be reported.
I can’t wait for ASCO this year to find out!
Lin, R., Hsieh, Y., Lin, P., Hsu, H., Chen, C., Tang, Y., Lee, C., & Wang, Y. (2010). The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients Journal of Clinical Investigation DOI: 10.1172/JCI40706
Vivanco, I., & Sawyers, C. (2002). The phosphatidylinositol 3-Kinase–AKT pathway in human cancer Nature Reviews Cancer, 2 (7), 489-501 DOI: 10.1038/nrc839
Massion, P. (2004). Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression American Journal of Respiratory and Critical Care Medicine, 170 (10), 1088-1094 DOI: 10.1164/rccm.200404-487OC
Turke, A., Zejnullahu, K., Wu, Y., Song, Y., Dias-Santagata, D., Lifshits, E., Toschi, L., Rogers, A., Mok, T., & Sequist, L. (2010). Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC Cancer Cell, 17 (1), 77-88 DOI: 10.1016/j.ccr.2009.11.022
Tang, Z., Du, R., Jiang, S., Wu, C., Barkauskas, D., Richey, J., Molter, J., Lam, M., Flask, C., Gerson, S., Dowlati, A., Liu, L., Lee, Z., Halmos, B., Wang, Y., Kern, J., & Ma, P. (2008). Dual MET–EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer British Journal of Cancer, 99 (6), 911-922 DOI: 10.1038/sj.bjc.6604559