Quantifying the sensitivities of EGF receptor (EGFR) tyrosine kinase inhibitors in drug resistant non-small cell lung cancer (NSCLC) cells using hydrogel-based peptide array.
Epidermal growth factor receptor (EGFR) signaling plays an important role in non-small cell lung cancer (NSCLC) and therapeutics targeted against EGFR have been effective in treating a subset of patients bearing somatic EFGR mutations. However, the cancer eventually progresses during treatment with EGFR inhibitors, even in the patients who respond to these drugs initially. A large variety of distinct irreversible inhibitors have been developed, which may combat therapeutic resistance. Nonetheless, major challenges in tailoring patient-specific treatment regimens involve predicting the most effective inhibitors and monitoring for acquisition of resistance. A patient-customized, predictive diagnostic that quantifies the effects of specific anti-EGFR therapies may improve outcomes in cancers where EGFR plays a mechanistic role. In this study we used an EGFR-phosphorylatable peptide, AEEEEYFELVAKKK, immobilized within a polyacrylamide hydrogel as a substrate for profiling the activation status of EGFR in the cellular extracts of erlotinib-resistant cancer cells. The hydrogel array was able to detect therapeutic resistance as well as identify inhibitors capable of combating therapeutic resistance. These findings establish the potential of this protein-acrylamide copolymer hydrogel array to not only evaluate EGFR status in cancer cell lysates but also to screen for the most promising therapeutics for individual patients and monitor effects of treatment on acquisition of resistance to EGFR inhibitors.
Ghosh
Gargi
G
Department of Chemical and Biological Engineering, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706, United States.
Yan
Xiaoliang
X
Lee
Andrew G
AG
Kron
Stephen J
SJ
Palecek
Sean P
SP
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000295:instrumentation*; D004867:Equipment Design; D019544:Equipment Failure Analysis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D040081:Protein Array Analysis / Q000295:instrumentation*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D020100:Hydrogels; D010455:Peptides; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases