Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors.

Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Patients with NSCLC are diagnosed at a locally advanced or metastatic stage where prognosis with palliative chemotherapy is poor. The discovery of epidermal growth factor receptor (EGFR) mutations has revolutionized cancer treatment for NSCLC by promoting the development of molecularly targeted therapies like tyrosine kinase inhibitors (TKIs). This review summarizes the clinical efficacy and tolerability of EGFR-TKIs, including osimertinib, in EGFR-mutated advanced NSCLC. EGFR-TKIs have demonstrated superior response and overall survival rates compared with chemotherapy in EGFR-mutated NSCLC. However, despite the initial rapid and durable clinical responses, acquired resistance to first- and second-generation TKIs eventually develops in most cases, with disease progression observed mostly within 12 months of treatment initiation. Osimertinib, a potent third-generation TKI, irreversibly inhibits mutated EGFR alleles, including T790M. In addition to longer survival and higher response rate, osimertinib has a favorable safety profile with a lower incidence of grade ≥3 treatment-related adverse events compared with other TKIs. Based on the efficacy and safety results, recently the National Comprehensive Cancer Network (NCCN) has included osimertinib as the "preferred first-line of treatment" in patients with metastatic EGFR mutationpositive NSCLC. Thus, osimertinib as first-line therapy for EGFRpositive patients irrespective of the T790M mutation status could be an ideal choice in the Indian setting where only 50% of patients opt for any second-line therapy after first-line failure.

A phase 3, randomized, double-blind study of single-dose fosaprepitant for prevention of cisplatin-induced nausea and vomiting: results of an Indian population subanalysis.

CONTEXT: Currently, there is limited data on the prevention of chemotherapy-induced nausea and vomiting (CINV) in Indian patients. AIMS: This post hoc study assessed the efficacy and safety of fosaprepitant compared with aprepitant for prevention of CINV in the Indian population. A subgroup analysis was performed from data collected in a phase 3 study of intravenous (IV) fosaprepitant or oral aprepitant, plus the 5-HT 3 antagonist ondansetron and the corticosteroid dexamethasone, in cisplatin-naοve patients with solid malignancies. MATERIALS AND METHODS: Patients scheduled to receive cisplatin (≥70 mg/m 2 ) were administered a single IV dose of fosaprepitant dimeglumine (150 mg) on day 1 or a 3-day dosing regimen of oral aprepitant (day 1:125 mg, days 2 and 3:80 mg) with standard doses of ondansetron and dexamethasone. Patients recorded nausea and/or vomiting episodes and their use of rescue medication and were monitored for adverse events (AEs) and tolerability. STATISTICAL ANALYSIS USED: Differences in response rates between fosaprepitant and aprepitant were calculated using the Miettinen and Nurminen method. RESULTS: In the Indian subpopulation (n = 372), efficacy was similar for patients in both the fosaprepitant or aprepitant groups; complete response in the overall, acute, and delayed phases and no vomiting in all phases were approximately 4 percentage points higher in the fosaprepitant group compared with the aprepitant group. Fosaprepitant was generally well-tolerated; common AEs were similar to oral aprepitant. CONCLUSIONS: IV fosaprepitant is as safe and effective as oral aprepitant in the Indian subpopulation and offers an alternative to the oral formulation.

Retinal axon target selection in Drosophila is regulated by a receptor protein tyrosine phosphatase.

Different Drosophila photoreceptors (R cells) connect to neurons in different optic lobe layers. R1-R6 axons project to the lamina; R7 and R8 axons project to separate layers of the medulla. We show a receptor tyrosine phosphatase, PTP69D, is required for lamina target specificity. In Ptp69D mutants, R1-R6 project through the lamina, terminating in the medulla. Genetic mosaics, transgene rescue, and immunolocalization indicate PTP69D functions in R1-R6 growth cones. PTP69D overexpression in R7 and R8 does not respecify their connections, suggesting PTP69D acts in combination with other factors to determine target specificity. Structure-function analysis indicates the extracellular fibronectin type III domains and intracellular phosphatase activity are required for targeting. We propose PTP69D promotes R1-R6 targeting in response to extracellular signals by dephosphorylating substrate(s) in R1-R6 growth cones.

The Drosophila SH2-SH3 adapter protein Dock is expressed in embryonic axons and facilitates synapse formation by the RP3 motoneuron.

The Dock SH2-SH3 domain adapter protein, a homolog of the mammalian Nck oncoprotein, is required for axon guidance and target recognition by photoreceptor axons in Drosophila larvae. Here we show that Dock is widely expressed in neurons and at muscle attachment sites in the embryo, and that this expression pattern has both maternal and zygotic components. In motoneurons, Dock is concentrated in growth cones. Loss of zygotic dock function causes a selective delay in synapse formation by the RP3 motoneuron at the cleft between muscles 7 and 6. These muscles often completely lack innervation in late stage 16 dock mutant embryos. RP3 does form a synapse later in development, however, because muscles 7 and 6 are normally innervated in third-instar mutant larvae. The absence of zygotically expressed Dock also results in subtle defects in a longitudinal axon pathway in the embryonic central nervous system. Concomitant loss of both maternally and zygotically derived Dock dramatically enhances these central nervous system defects, but does not increase the delay in RP3 synaptogenesis. These results indicate that Dock facilitates synapse formation by the RP3 motoneuron and is also required for guidance of some interneuronal axons The involvement of Dock in the conversion of the RP3 growth cone into a presynaptic terminal may reflect a role for Dock-mediated signaling in remodeling of the growth cone's cytoskeleton.

Kinesin light chains are essential for axonal transport in Drosophila.

Kinesin is a heterotetramer composed of two 115-kD heavy chains and two 58-kD light chains. The microtubule motor activity of kinesin is performed by the heavy chains, but the functions of the light chains are poorly understood. Mutations were generated in the Drosophila gene Kinesin light chain (Klc), and the phenotypic consequences of loss of Klc function were analyzed at the behavioral and cellular levels. Loss of Klc function results in progressive lethargy, crawling defects, and paralysis followed by death at the end of the second larval instar. Klc mutant axons contain large aggregates of membranous organelles in segmental nerve axons. These aggregates, or organelle jams (Hurd, D.D., and W.M. Saxton. 1996. Genetics. 144: 1075-1085), contain synaptic vesicle precursors as well as organelles that may be transported by kinesin, kinesin-like protein 68D, and cytoplasmic dynein, thus providing evidence that the loss of Klc function blocks multiple pathways of axonal transport. The similarity of the Klc and Khc (. Cell 64:1093-1102; Hurd, D.D., and W.M. Saxton. 1996. Genetics 144: 1075-1085) mutant phenotypes indicates that KLC is essential for kinesin function, perhaps by tethering KHC to intracellular cargos or by activating the kinesin motor.

A complex translocation involving chromosomes 2, 9 and 22 in a patient with chronic myeloid leukemia.

A patient with a high leukocyte count, diagnosed with chronic myeloid leukemia was referred for cytogenetic study. Peripheral blood and bone marrow cells were cultured without mitogenic stimulation. All karyotypes represented rare, varient Philadelphia chromosome with-three way translocation, i.e. t (2; 9; 22) (p13; q34; q11).

Competition and cooperation among receptor tyrosine phosphatases control motoneuron growth cone guidance in Drosophila.

The neural receptor tyrosine phosphatases DPTP69D, DPTP99A and DLAR are involved in motor axon guidance in the Drosophila embryo. Here we analyze the requirements for these three phosphatases in growth cone guidance decisions along the ISN and SNb motor pathways. Any one of the three suffices for the progression of ISN pioneer growth cones beyond their first intermediate target in the dorsal muscle field. DLAR or DPTP69D can facilitate outgrowth beyond a second intermediate target, and DLAR is uniquely required for formation of a normal terminal arbor. A different pattern of partial redundancy among the three phosphatases is observed for the SNb pathway. Any one of the three suffices to allow SNb axons to leave the common ISN pathway at the exit junction. When DLAR is not expressed, however, SNb axons sometimes bypass their ventrolateral muscle targets after leaving the common pathway, instead growing out as a separate bundle adjacent to the ISN. This abnormal guidance decision can be completely suppressed by also removing DPTP99A, suggesting that DLAR turns off or counteracts a DPTP99A signal that favors the bypass axon trajectory. Our results show that the relationships among the tyrosine phosphatases are complex and dependent on cellular context. At growth cone choice points along one nerve, two phosphatases cooperate, while along another nerve these same phosphatases can act in opposition to one another.

Tyrosine phosphorylation and axon guidance: of mice and flies.

Recent genetic evidence suggests that tyrosine kinases and tyrosine phosphatases can control the guidance of specific growth cones. Within a family of related phosphatases or kinases, individual members can have partially redundant functions. Receptor phosphatases can work together at one guidance choice point, but in opposition at another. The specific combination of kinases and phosphatases active in a growth cone may be an important determinant of pathway choice. One mechanism by which these proteins could control guidance decisions is through regulation of adhesion between growth cones and axons.

Receptor tyrosine phosphatases are required for motor axon guidance in the Drosophila embryo.

The receptor tyrosine phosphatases DPTP69D and DPTP99A are expressed on motor axons in Drosophila embryos. In mutant embryos lacking DPTP69D protein, motor neuron growth cones stop growing before reaching their muscle targets, or follow incorrect pathways that bypass these muscles. Mutant embryos lacking DPTP99A are indistinguishable from wild type. Motor axon defects in dptp69D dptp99A double mutant embryos, however, are much more severe than in embryos lacking only DPTP69D. Our results demonstrate that DPTP69D and DPTP99A are required for motor axon guidance and that they have partially redundant functions during development of the neuro-muscular system.

A Drosophila receptor tyrosine phosphatase expressed in the embryonic CNS and larval optic lobes is a member of the set of proteins bearing the "HRP" carbohydrate epitope.

Recent studies have defined several cell surface glycoproteins expressed in the developing nervous system of insect embryos that may be involved in axon outgrowth and guidance processes. These glycoproteins include the fasciclins and a group of receptor-linked protein tyrosine phosphatases (R-PTPs). In embryos, the fasciclins are localized to axonal subsets, while the R-PTPs appear to be expressed on most or all CNS axons. To identify other neuronal cell surface glycoproteins in the Drosophila embryo, we have taken a biochemical approach. This is based on the observation that antisera against horseradish peroxidase (HRP) recognize a carbohydrate epitope that is selectively expressed in the insect nervous system. A large number of neuronal glycoproteins (denoted "HRP proteins") apparently bear the HRP carbohydrate epitope. We have used polyclonal anti-HRP antibodies to purify these proteins from Drosophila embryos, and have obtained protein sequences from seven HRP protein bands. These data define three major HRP proteins as neurotactin, fasciclin I, and an R-PTP, DPTP69D. Western blotting data suggest that fasciclin II, neuroglian, DPTP10D, and DPTP99A are also HRP proteins. We show that DPTP69D, like the previously characterized R-PTPs, is localized to CNS axons in the embryo. In third instar larvae, DPTP69D expression is restricted to subsets of neuronal processes in the brain, ventral nerve cord, and eye disk. In the optic lobes, DPTP69D is localized to the neuropils of the lamina and medulla, and to an array of parallel thick bundles that may be the transmedullary fibers of the developing lobula complex.