The era of molecularly targeted therapy in lung cancer began in

The era of molecularly targeted therapy in lung cancer began in 2004 using the discovery that activating epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) correlated with clinical response to EGFR tyrosine kinase inhibitors (TKIs) [1-3] although EGFR TKIs were developed and approved for clinical use prior to the knowledge of these activating EGFR mutations [4 5 Subsequently five randomized trials in patients with NSCLC with activating EGFR mutations have proven statistically significant superior response rates and progression-free survival for EGFR TKIs compared with standard doublet chemotherapy [6-10]. Rabbit Polyclonal to MSK2 (phospho-Thr568). for the recognition of other driver mutations in NSCLC. In the Iressa Pan-Asia Study (IPASS) [13 14 and First-SIGNAL [15] tests despite JNK-IN-8 IC50 the enrichment of Asian woman never-smokers with adenocarcinoma and the employment of sophisticated sequencing techniques only approximately 60% and 44% of individuals in each study respectively were found to carry activating EGFR mutations indicating that additional potential driver mutations remain to be discovered [16]. Finding of Anaplastic Lymphoma Kinase Rearrangement in the Pathogenesis of NSCLC ALK rearrangements were recognized in NSCLC in 2007 by two self-employed groups. Soda et al. developed retroviral-based cDNA expression libraries to JNK-IN-8 IC50 screen for novel oncogenes [17 18 They transfected a cDNA library derived from a lung adenocarcinoma from a 62-year-old Japanese male smoker who was prescreened to be negative for KRAS and EGFR mutations [17]. They identified an echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (EML4-ALK) fusion transcript that possessed transforming activity in 3T3 cells [17]. 3T3 cells transfected with EML4-ALK and implanted in nude mice resulted in rapid tumor growth [17]; an ALK inhibitor inhibited the growth of BA/F3 cells transfected with EML4-ALK. Finally a preliminary survey of a panel of 33 NSCLC tumors revealed that EML4-ALK rearrangement occurs independently of EGFR and KRAS mutations [17]. To further demonstrate the role of EML4-ALK in the pathogenesis of NSCLC Soda et al. generated transgenic mice engineered to specifically express EML4-ALK in lung alveolar cells which resulted in hundreds of lung adenocarcinoma nodules. Treatment of the transgenic mice with an ALK inhibitor led to decreased tumor burden weighed against neglected mice. Intravenous shot of EML4-ALK/3T3 cells led to substantial infiltration of EML4-ALK/3T3 cells within the lungs of nude mice and fast death of a lot of the mice JNK-IN-8 IC50 within one month [18]. Treatment using the same ALK inhibitor led to the lack of EML4-ALK/3T3 cells within the lung and long term survival [18]. In conclusion Soda pop et JNK-IN-8 IC50 al. convincingly proven that EML4-ALK can be a unique drivers mutation in NSCLC which inhibition of EML4-ALK activity in vivo resulted in the reduced amount of lung tumor burden. Rikova et al contemporaneously. characterized the phosphotyrosine profile in 191 NSCLC cell lines and tumor examples utilizing a phosphoproteomic method of identify “drivers kinases” in NSCLC [19]. They determined a high degree of ALK phosphorylation in a number of NSCLC tumor examples and H2228 NSCLC cells. Quick amplification from the 5′ complementary DNA ends (5′ Competition) from the RNA transcripts isolated from these examples with extremely phosphorylated ALK exposed the EML4-ALK fusion transcript [19]. No mutations had been found in the ALK kinase domain [19]. Thus two groups using two different approaches independently identified ALK translocation the first of its kind in a common solid malignancy. The Normal Physiological Role of ALK and Signal Transduction Pathways Activated by EML4-ALK The full-length ALK cDNA contains 29 exons. The full-length ALK protein contains 1 620 amino acids with a predicted molecular weight of 177 kilodaltons (kDa) [20]. The 254-amino acid kinase domain comprises amino acid residues 1123-1376 preceded by a short transmembrane region of amino acids 1031-1058 [20]. ALK is temporally and spatially expressed during development of the murine neonatal central nervous JNK-IN-8 IC50 system with its expression highest in the neonatal brain and is not expressed in any non-neural tissues during any stage of development of the mouse [20 21 ALK was so named when it was discovered to be translocated in anaplastic large cell lymphoma (ALCL) [22]. Subsequently ALK rearrangement with various fusion partners has been discovered in diffuse large B-cell lymphoma and inflammatory myofibroblastic tumor (IMT) prior to the discovery of ALK rearrangement in NSCLC. All three of the major signaling pathways (PI3K-AKT RAS-ERK JAK-STAT3) have been identified as being engaged by the various ALK fusion proteins [23 24 Much less is known about the normal function of the native ALK protein. Based on its expression design [21 22 ALK can be thought to be involved with early neurogenesis. In Drosophila the ligand for ALK is stomach but zero jelly.