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 (, 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.


Solit D, Sawyers CL. Drug discovery: How melanomas bypass new therapy. Nature. 2010 Dec 16;468(7326):902-3. PubMed PMID: 21164474.

Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-1037.

Roumiantsev S, Shah NP, Gorre ME, Nicoll J, Brasher BB, Sawyers CL, Van Etten RA. Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10700-5. Epub 2002 Jul 29. PubMed PMID: 12149456; PubMed Central PMCID: PMC125018.

Shah NP, Nicoll JM, Nagar B, Gorre ME, Paquette RL, Kuriyan J, Sawyers CL. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002 Aug;2(2):117-25. PubMed PMID: 12204532.

Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004 Jul 16;305(5682):399-401. PubMed PMID: 15256671.

Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A, Huntly B, Fabbro D, Fendrich G, Hall-Meyers E, Kung AL, Mestan J, Daley GQ, Callahan L, Catley L, Cavazza C, Azam M, Neuberg D, Wright RD, Gilliland DG, Griffin JD. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005 Feb;7(2):129-41. Erratum in: Cancer Cell. 2005 Apr;7(4):399. Mohammed, Azam [corrected to Azam, Mohammad]. PubMed PMID: 15710326.

Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz JA, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Shou Y, Gallagher NJ, Blakesley R, Baccarani M, Cortes J, le Coutre PD. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase following imatinib resistance or intolerance: 24-month follow-up results. Blood. 2010 Nov 22. [Epub ahead of print] PubMed PMID: 21098399.

Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O’Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41. PubMed PMID: 16775234.

Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O’Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Nov 15;110(10):3540-6. Epub 2007 Aug 22. PubMed PMID: 17715389.

Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, Shen Z, Mayer J, Pasquini R, Nakamae H, Huguet F, Boqué C, Chuah C, Bleickardt E, Bradley-Garelik MB, Zhu C, Szatrowski T, Shapiro D, Baccarani M. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2260-70. Epub 2010 Jun 5. PubMed PMID: 20525995.

Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9. Epub 2010 Jun 5. PubMed PMID: 20525993.

Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton  MR, Futreal PA. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun 27;417(6892):949-54. Epub 2002 Jun 9. PubMed PMID: 12068308.

Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010 Dec 16;468(7326):968-72. Epub 2010 Nov 24. PubMed PMID: 21107320.

Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010 Dec 16;468(7326):973-7. Epub 2010 Nov 24. PubMed PMID: 21107323.