Until recently, the molecular mechanisms underlying the sensitivity of tyrosine kinase inhibitors remained unknown. Paradoxical associations between EGFR expression and response to treatment lead to further confusion regarding determinants of response to therapy. Recently demonstrated in nonsmall cell lung cancer was the observation that specific mutations in the EGFR tyrosine kinase domain predicted for response to treatment with agents that block EGFR receptors. Two separate study groups (98,99) reported the discovery and the identification of missense and deletion mutations that cause the EGFR to have a much higher affinity for gefitinib and hence lead to an increased responsiveness to the tyrosine kinase inhibitor. Recently reported were the results of Lee et al. (100) who investigated the presence of somatic mutations of ErbB2 kinase domain in gastric, colorectal, and breast carcinomas. The authors concluded that in addition to lung adeno-carcinomas, ErbB2 kinase domain mutations occur in breast cancers in addition to other cancers.
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