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ALK: A Driver of Cancer Pathogenesis1

ALK gene rearrangements are the primary drivers of disease in ALK+ NSCLC2

ALK-mediated signaling role in NSCLC progression and development chart

AKT=AKT8 virus oncogene cellular homolog; ALK=anaplastic lymphoma kinase; BAD=bcl-2–associated death promoter protein; EML4=echinoderm microtubule-associated protein-like 4; ERK=extracellular signal-regulated kinase; IP3=inositol trisphosphate; MEK=mitogen-activated protein kinase/ERK kinase; mTOR=mammalian target of rapamycin; NSCLC=non-small cell lung cancer; PI3K=phosphatidylinositol 3-kinase; PIP2=phosphatidylinositol 3,4-bisphosphate; PLC-γ=phospholipase C-γ; Ras=rat sarcoma; S6K=S6 kinase; STAT3/5=signal transducer and activator of transcription 3/5.

Adapted by permission from Macmillan Publishers Ltd: Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014;95:15-23, copyright 2014.

  • In ALK+ non-small cell lung cancer (NSCLC), the ALK gene undergoes a rearrangement, called a translocation, within the chromosome to create a fusion between ALK and another gene2
Chromosomal translocation
  • EML4-ALK is the most common ALK fusion in lung cancer, although several other ALK fusions have been reported3
  • ALK gene rearrangements occur in approximately 5% of patients with NSCLC2

ALK fusion proteins are constitutively active, promoting downstream signaling pathways involved in the proliferation and survival of tumor cells3

  • Independent of ligand binding, EML4—or the partner protein—facilitates dimerization of the fusion protein, resulting in the constitutive activation of the ALK kinase domain4
  • At the cellular level, the ALK fusion protein may become the sole regulator of critical downstream signaling pathways, such as the Ras/MAPK, PI3K/AKT, and JAK/STAT pathways2

ALK is an established target in ALK-rearranged NSCLC2,5

  • Tumor cells harboring the ALK rearrangement become dependent on ALK, a key regulator of tumor cell growth and survival5
  • ALK is minimally expressed in normal tissues6

Many patients with ALK+ NSCLC will progress in the CNS5,9

  • In up to 46% of ALK+ NSCLC patients, the CNS is the first site of progression while receiving an ALK-directed therapy9,10
  • Smaller aggregates of metastatic tumor cells, or "micrometastases," are able to cross the blood-brain barrier with minimal disruption, allowing them to continue to grow and reach a clinically significant size13
  • Since conventional scans can only detect lesions that have reached a size within specific resolution capacity, micrometastases may go undetected12

The blood-brain barrier removes small molecules from the CNS through efflux activity11,13

  • The blood-brain barrier forms a CNS sanctuary for metastatic disease11
  • The blood-barrier is reinforced by P-gp, a drug-efflux-transporter protein, which actively removes a broad range of P-gp substrates from the endothelial cell cytoplasm before they cross into the CNS11

Certain transporter proteins may prevent small molecules from crossing the blood-brain barrier13

ALK blood-brain barrier

Reprinted from NeuroRx, Vol 2/edition 1, Löscher W, Potschka H, Blood-brain barrier active efflux transporters: ATP-binding cassette gene family, 86-98, Copyright 2005, with permission from Elsevier.

Significant morbidity is associated with CNS metastasis14

Significant neurological signs and symptoms related to the location and extent of brain involvement occur in most patients14

ALK+ non-small cell lung cancer resistance mechanisms

Multiple mechanisms may promote resistance in ALK+ NSCLC3

ALK resistance mechanisms to ALK positive NSCLC graph

Reused with permission. © 2014 American Society of Clinical Oncology. All rights reserved.

ALK-dependent mechanisms, such as secondary mutations of the ALK kinase domain and amplification of the ALK fusion gene, may promote resistance3

  • The gatekeeper mutation L1196M is the most commonly reported resistance mutation believed to impact the ALK kinase domain2,3
  • Other mutations such as C1156Y, G1202R, S1206Y, L1152R, F1174L, G1269A, and 1151Tins may also play a role in resistance3,5,15

Resistance may also be driven by ALK-independent mechanisms such as the activation of alternative signaling pathways2

Activation of alternative pathways bypasses ALK2

Activation of alternative pathways

Adapted by permission from Macmillan Publishers Ltd: Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014;95:15-23, copyright 2014.

  • Upregulation of EGFR-signaling has been observed in resistant ALK+ cell lines2
  • Increased EGFR activation has been detected in patients with ALK+ NSCLC who developed resistance5
  • Other mechanisms, including c-KIT and KRAS, have also been identified as potential bypass tracks in resistance3
    A
    Anaplastic lymphoma kinase (ALK)

    The ALK gene encodes a receptor tyrosine kinase in the insulin receptor superfamily. While the normal physiological role of ALK is poorly understood, the expression pattern of ALK suggests an important role in the development of the nervous system.

    B
    Blood-brain barrier

    A mechanism found across species that protects the brain from exposure to toxins, both exogenous and endogenous.

    C
    C-kit

    A stem cell factor receptor. C-kit is a type of receptor tyrosine kinase that may be found in higher levels on some types of cancer cells. It is also a type of tumor marker.

    F
    Fluorescence in situ hybridization (FISH)

    Cytogenetic technique used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high degree of sequence complementarity.

    G
    Gatekeeper gene

    Gene responsible for controlling, or inhibiting, cell growth; generally referred to as a tumor-suppressor gene.

    Gatekeeper mutation

    A mutation of the gatekeeper region in the kinase domain that is commonly involved in acquired resistance.

    Gene amplification

    The multiple replication of a section of the genome, which occurs during a single cell cycle and results in the production of many copies of a specific DNA sequence.

    I
    Immunohistochemistry

    Uses antibodies to detect the target protein on tissue sections.

    P
    P-glycoprotein

    A transporter protein that serves as an efflux pump to extrude substrates back into circulation after they initially diffuse into the endothelial cells in the brain capillary.

    R
    Reverse transcriptase-polymerase chain reaction (RT-PCR)

    Detects ALK by determining the presence of specific messenger RNA (mRNA) transcripts.

    T
    Tmax

    The time to reach maximum plasma concentration of a drug after administration.

    Translocation

    Transposition of 2 segments between nonhomologous chromosomes as a result of abnormal breakage and refusion of reciprocal segments.

    Tumorigenesis

    The production or formation of a tumor or tumors.

    • Pulford K, Morris SW, Turturro F. Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol. 2004;199:330-358. PMID: 15095281

      Pulford K, Morris SW, Turturro F. Anaplastic lymphoma kinase proteins in growth control and cancer. J Cell Physiol. 2004;199:330-358. PMID: 15095281

    • Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014;95:15-23. PMID: 24091716

      Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014;95:15-23. PMID: 24091716

    • Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013;31:1105-1111. PMID: 23401436

      Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol. 2013;31:1105-1111. PMID: 23401436

    • Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-1203. PMID: 18083107

      Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190-1203. PMID: 18083107

    • Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17. doi:10.1126/scitranslmed.3003316. PMID: 22277784

      Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Sci Transl Med. 2012;4:120ra17. doi:10.1126/scitranslmed.3003316. PMID: 22277784

    • Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19:679-690. PMID: 21575866

      Sakamoto H, Tsukaguchi T, Hiroshima S, et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011;19:679-690. PMID: 21575866

    • Rangachari D, Yamaguchi N, VanderLaan PA, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1):108-111.

      Rangachari D, Yamaguchi N, VanderLaan PA, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer. 2015;88(1):108-111.

    • Kang HJ, Lim HJ, Park JS, et al. Comparison of clinical characteristics between patients with ALK-positive and EGFR-positive lung adenocarcinoma. Respir Med. 2014;108(2):388-394.

      Kang HJ, Lim HJ, Park JS, et al. Comparison of clinical characteristics between patients with ALK-positive and EGFR-positive lung adenocarcinoma. Respir Med. 2014;108(2):388-394.

    • Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7:1807-1814. PMID: 23154552

      Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol. 2012;7:1807-1814. PMID: 23154552

    • Yoshida T, Oya Y, Tanaka K, et al. 2016;97:43-47.

      Yoshida T, Oya Y, Tanaka K, et al. 2016;97:43-47.

    • Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663-1674. PMID: 17363519

      Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res. 2007;13:1663-1674. PMID: 17363519

    • Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: AACP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(suppl 3):178S-201S. PMID: 17873168

      Silvestri GA, Gould MK, Margolis ML, et al. Noninvasive staging of non-small cell lung cancer: AACP evidence-based clinical practice guidelines (2nd edition). Chest. 2007;132(suppl 3):178S-201S. PMID: 17873168

    • Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86-98. PMID: 15717060

      Löscher W, Potschka H. Blood-brain barrier active efflux transporters: ATP-binding cassette gene family. NeuroRx. 2005;2:86-98. PMID: 15717060

    • Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2:2100-2137. PMID: 24281220

      Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010;2:2100-2137. PMID: 24281220

    • Kodama T, Tsukaguchi T, Yoshida M, Kondoh O, Sakamoto H. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett. 2014;351:215-221. PMID: 24887559

      Kodama T, Tsukaguchi T, Yoshida M, Kondoh O, Sakamoto H. Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett. 2014;351:215-221. PMID: 24887559

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