Arguably, the most exciting trend of the last decade in chemotherapy for tumors based on traditional small molecule agents is the use of drugs that target specific protein kinases that participate in signaling pathways crucial for tumor growth (Solit and Sawyers, 2010).  The first example was imatinib (Druker et al., 2001) for the treatment of chronic myeloid leukemia (CML).  Subsequently imatinib was found to inhibit two tyrosine kinases (KIT and PGGFRA) that are crucial for a different cancer, gastrointestinal stromal tumor.   In CML, imatinib proved effective and relatively non-toxic but not curative (Solit and Sawyers, 2010).  One problematic aspect of therapy with imatinib was the development of tumor cell resistance (Shah et al., 2002).  Investigation of the genetic origin of resistance to imatinib revealed mutations in the target kinase, BCR-ABL (Shah et al., 2002).  This knowledge permitted development of second-generation inhibitiors (dasatinib and nilotinib) of the same kinase (Shah et al., 2004; Weisberg et al., 2005) that can be used in case of failed treatment with imatinib (Kantarjian et al., Blood 2010) and appear to have therapeutic advantages (over imatinib) including greater potency and reduced risk of eliciting resistance (Talpaz et al., 2006; Kantarjian et al., 2007; Kantarjian et al., NEJM 2010; Saglio et al., 2010).

In the case of the most lethal skin cancer (http://www.skincancer.org/Melanoma/), melanoma, the serine/threonine kinase, B-RAF, was shown to be mutated in greater than 60% of tumors.  The most common tumor-associated mutation (V600E; i.e., valine to glutamic acid at amino acid 600) was demonstrated to increase signaling through the downstream effectors MEK and ERK, consistent with a causal role for the V600E B-RAF mutation in melanoma (Davies et al., 2002).   As occurred with imatinib treatment of patients suffering from CML, however, treatment of melanoma patients with an inhibitor (PLX4032) of the mutated B-RAF led to tumor resistance.Two new studies (Johannessen et al., 2010; Nazarian et al., 2010) reveal the mutational mechanisms for this resistance.  What is of particular interest is that the functionally meaningful mutations in PLX4032-resistant melanomas are not in B-RAF.  Instead, the mutations affect other kinases that bypass B-RAF.  In some cases, these mutations yield signaling through the same “downstream” effector proteins (MEK and ERK) activated by normal or mutated B-RAF.  Other mutations result in similar functional effects by an apparently “parallel pathway.”  Thus, in the case of melanoma, tumor cell evolution effectively illustrates the opportunistic nature of evolution through mutation and selection.

Presumably, oncologists interested in improving therapy for melanoma will likely seek to emulate their colleagues who developed second-generation inhibitors of BCR-ABL for the treatment of CML by developing new kinase inhibitors.  However, in this case, the second-generation agents might well target kinases other than B-RAF.  One option suggested by Solit and Sawyers is to use combination chemotherapy to simultaneously inhibit mutated B-RAF and MEK, which is the final common pathway for tumor-supporting signaling for most but not all of the PLX4032-resistance mechansisms.  Perhaps oncologists will also evolve in their approach to drug development by taking account of the possibilities (or is it inevitabilities?) for the development of tumor cell resistance to essential kinase inhibitors after the initial identification of lead compounds.

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