Mechanisms of targeted therapy resistance in lung cancer

Institution:	University of California, Los Angeles
Investigator(s):	Kostyantyn Krysan, Ph.D.
Award Cycle:	2006 (Cycle 15)	Grant #: 15RT-0152	Award: $358,500
Subject Area:	Cancer
Award Type:	Research Project Awards

Abstracts

Initial Award Abstract

Lung cancer, which accounts for more than 28 percent of all cancer deaths each year, is the leading cause of cancer related mortality in the United States. Studies of human cancers have revealed frequent overexpression of cyclooxygenase-2 (COX-2) enzyme in a variety of different malignancies. Overexpression of COX-2 can stimulate cell growth and invasion and promote tumor cell survival. A COX-2 product abundantly present in the lung cancer microenvironment, prostaglandin E2 (PGE2) is an important mediator of immune regulation and cellular survival.

The Epidermal Growth Factor Receptor (EGFR) is an important target for anti-cancer therapies. Several EGFR Tyrosine Kinase (TK) inhibitors are being evaluated and in addition, two have recently been FDA approved for treatment of lung cancer. However, the inherent problem in the biology of lung cancer is the resistance of lung cancer cells to targeted therapies due to which only a limited population of lung cancer patients responds to the EGFR TK inhibitors. In a significant number of cases tumor re-growth after initial regression by EGFR TK inhibitor therapy has been reported. Understanding the mechanisms of this resistance will likely lead to important advances in therapy for this devastating disease.

Recent reports indicate two possible mechanisms for EGFR inhibitor resistance — somatic mutations in the receptor’s tyrosine kinase domain and activation of the downstream components of EGFR pathway by cross-talk from other types of receptors. Understanding the mechanisms of Non-Small Cell lung Cancer (NSCLC) resistance to EGFR inhibition will lead to important advances in therapy for this devastating disease. Our efforts are therefore focused on investigation of the cross-talk between the components of EGFR pathway and other signal transduction pathways that can overcome pharmacological inhibition of EGFR by activation of its downstream components.

Our preliminary data clearly demonstrate that PGE2 via its receptor is able to activate the EGFR pathway in a subset of NSCLC cell lines in an EGFR-independent manner. Our results indicate that this activation was resistant to EGFR inhibitors including erlotinib (Tarceva®) and was not evident in bronchial epithelial cells. The functional manifestation of such activation was enhanced NSCLC cell proliferation in response to PGE2 treatment that was resistant to the EGFR inhibition. Our preliminary data highlight the complex network of cross-signaling that can shift the balance between stimulatory and inhibitory responses in NSCLC toward pro-survival and proliferative phenotypes that ultimately may determine the cancer cell resistance to pharmacological growth factor receptor inhibition. These findings suggest that COX-2 overexpression may be an important contributor to EGFR inhibitor resistance in NSCLC. In the proposed study we will be studying the mechanisms that mediate EGFR pathway activation by PGE2.

Based on our laboratory findings, we conducted a phase I clinical trial evaluating the combination of erlotinib and COX-2 inhibitor celecoxib in advanced NSCLC. The results of the phase I study revealed improved clinical responses above what is expected for erlotinib alone. These studies are important translational investigations because they will define the pathways responsible for the PGE2-dependent activation of EGFR pathway and help identify additional therapeutic targets and will likely lead to important advances in lung cancer treatment.

Publications

Cyclooxygenase-2-dependent regulation of E-cadherin expression PGE2 induces E-cadherin transcriptional repressors ZEB1 and SNAIL in NSCLC.
Periodical: Cancer Research			Index Medicus:
Authors: Krysan K				ART
Yr: 2006	Vol:	Nbr: 66	Abs:	Pg: 5338-5345

The Potential and Rationale for COX-2 Inhibitors in Lung Cancer
Periodical: Curr. Med. Chem			Index Medicus:
Authors: Krysan K, Reckamp KL, Sharma S, Dubinett SM				ART
Yr: 2006	Vol: 6	Nbr:	Abs:	Pg: 209-220

A phase I Trial to Determine the optimal Biologic Dose of Celecoxib when Combineed with Erlotinib in Advanced Non-Small Cell Lung Cancer.
Periodical: Clinical Cancer Research			Index Medicus:
Authors: Krysan K				ART
Yr: 2006	Vol:	Nbr: 12	Abs:	Pg: 3381-3388

Significance of cyclooxygenase -2 in prognosis targeted therapy and chemoprevention of NSCLC.
Periodical: Future Cardiol			Index Medicus:
Authors: Krysan K				ART
Yr: 2007	Vol:	Nbr: 3	Abs:	Pg: 149-153

Tumor response to combination celecoxib and erlotinib therapy in non-small cell lung cancer is associated with a low baseline matrix metalloproteinase (MMP)-9 and a decline in serum
Periodical: Journal of Thoracic Oncology			Index Medicus:
Authors: Reckamp, K.L., Gardner, B.K., Figlin, R.A., Elashoff, D., Krysan, K., Dohadwala, M., Mao,				ART
Yr: 2007	Vol: 3	Nbr:	Abs:	Pg: 117-124

Inflammation and lung carcinogenesis: applying new findings in prevention and treatment
Periodical: Expert Review of Anticancer Therapy			Index Medicus:
Authors: Peebles, K.A., Lee, J.M., Mao, J.T., Hazra, S., Reckamp, K.L., Krysan, K., Dohadwala, M.				ART
Yr: 2007	Vol: 7	Nbr:	Abs:	Pg: 1405-1421

Inflammation, EMT and EGFR TKI resistance
Periodical: Journal of Thoracic Oncology			Index Medicus:
Authors: Krysan, K., Lee, J.M., Dohadwala, M., Gardner, B.K., Reckamp, K.L., Garon, E., St. John, M				ART
Yr: 2008	Vol: 3	Nbr:	Abs:	Pg: 107-110

Cyclooxygenase-2-dependent regulation of E-cadherin expression PGE2 induces E-cadherin transcriptional repressors ZEB1 and SNAIL in NSCLC.
Periodical: Cancer Research			Index Medicus:
Authors: Krysan K				ART
Yr: 2006	Vol:	Nbr: 66	Abs:	Pg: 5338-5345

The Potential and Rationale for COX-2 Inhibitors in Lung Cancer
Periodical: Curr. Med. Chem			Index Medicus:
Authors: Krysan K, Reckamp KL, Sharma S, Dubinett SM				ART
Yr: 2006	Vol: 6	Nbr:	Abs:	Pg: 209-220

A phase I Trial to Determine the optimal Biologic Dose of Celecoxib when Combineed with Erlotinib in Advanced Non-Small Cell Lung Cancer.
Periodical: Clinical Cancer Research			Index Medicus:
Authors: Krysan K				ART
Yr: 2006	Vol:	Nbr: 12	Abs:	Pg: 3381-3388

Significance of cyclooxygenase -2 in prognosis targeted therapy and chemoprevention of NSCLC.
Periodical: Future Cardiol			Index Medicus:
Authors: Krysan K				ART
Yr: 2007	Vol:	Nbr: 3	Abs:	Pg: 149-153

Tumor response to combination celecoxib and erlotinib therapy in non-small cell lung cancer is associated with a low baseline matrix metalloproteinase (MMP)-9 and a decline in serum
Periodical: Journal of Thoracic Oncology			Index Medicus:
Authors: Reckamp, K.L., Gardner, B.K., Figlin, R.A., Elashoff, D., Krysan, K., Dohadwala, M., Mao,				ART
Yr: 2007	Vol: 3	Nbr:	Abs:	Pg: 117-124

Inflammation and lung carcinogenesis: applying new findings in prevention and treatment
Periodical: Expert Review of Anticancer Therapy			Index Medicus:
Authors: Peebles, K.A., Lee, J.M., Mao, J.T., Hazra, S., Reckamp, K.L., Krysan, K., Dohadwala, M.				ART
Yr: 2007	Vol: 7	Nbr:	Abs:	Pg: 1405-1421

Inflammation, EMT and EGFR TKI resistance
Periodical: Journal of Thoracic Oncology			Index Medicus:
Authors: Krysan, K., Lee, J.M., Dohadwala, M., Gardner, B.K., Reckamp, K.L., Garon, E., St. John, M				ART
Yr: 2008	Vol: 3	Nbr:	Abs:	Pg: 107-110