Virtual Library

Start Your Search

M. Childress



Author of

  • +

    MS 22 - Variety in the Oncogene (Does the Exact Mutation Matter?) (ID 40)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
    • +

      MS22.02 - ALK, ROS1, and RET - Does the Partner Gene Matter? (ID 1946)

      14:15 - 15:45  |  Author(s): M. Childress

      • Abstract
      • Presentation

      Abstract:
      Chromosomal rearrangements involving the ALK, ROS1, RET, and NTRK1 tyrosine kinases with several different gene fusion partners have been identified as therapeutically actionable genomic alterations in collectively up to 10% of non-small cell lung cancer (NSCLC) [1-4]. Notably, these kinase fusions have also been detected in several other epithelial, hematologic, neural, and mesenchymal malignancies, underscoring the importance of understanding fusion kinase biology in order to develop the most effective therapeutic strategies. In fact, numerous studies have now shown that tumors which harbor ALK, ROS1, RET, or NTRK1 fusions exhibit a dependency on the activated tyrosine kinase for proliferation and survival. This dependency, or ‘oncogene addiction’, makes the cancer highly sensitive to small molecule tyrosine kinase inhibitors (TKIs). In particular, ALK serves as the paradigm for therapeutically targetable kinase fusions in NSCLC. Crizotinib was the first ALK TKI to be approved for treatment of patients with ALK fusion positive (ALK+) NSCLC. Several other ALK TKIs, including ceritinib, alectinib, X-396, brigatinib, ASP3026, and PF-06463922 are also being developed for the treatment of ALK+ malignancies. These ‘next-generation’ ALK TKIs typically have more on-target efficacy against the ALK kinase domain and are able to overcome some of the crizotinib resistance mutations which have been observed clinically. While much emphasis has been placed on the study of the tyrosine kinase portion of ALK, ROS1, RET, and NTRK1 fusions, less is known about the 5’ gene fusion partners. However, the biology of the 5’ gene fusion partner is essential for driving the expression and function of the kinase fusion. Numerous different 5’ gene partners have been identified for each of the kinase fusions in NSCLC (Table 1). For example, EML4 is the most common fusion partner for ALK in NSCLC; however, KIF5B, TFG, KLC1, PTPN3, STRN, and SQSTM1 have also been identified as ALK partner genes in this disease. To add to the complexity, more than 10 different EML4-ALK fusions have been detected in NSCLC, varying by the extent of the EML4 gene which is fused to ALK. Likewise, numerous gene fusion partners have been described for ROS1, RET, and NTRK1 fusions in lung cancer (Table 1). Although the fusion partners can vary, they share three basic features. First, the promoter of the 5’ fusion partner dictates the expression of the fusion. Second, most fusion partners contribute an oligomerization domain, which can aid in auto-activation of the kinase [5]; although, this has not been verified for all fusion partners. The most common oligomerization domain found in the fusion partners is the coiled-coil domain. EML4-ALK homodimerizes by virtue of a coiled-coil domain in EML4. Disruption of this domain abrogates the ability of EML4-ALK to transform cells [5]. Furthermore, the extent of oligomerization may be important for transformation; some fusions dimerize, trimerize [6], or form tetramers [7]. Lastly, the 5’ gene fusion partner also determines subcellular localization of the fusion, and this can have significant effects on the interaction of the kinase fusion with other cellular proteins, influencing activation, signaling, function, and degradation of the fusion. For example, a thorough structural analysis of the most common EML4-ALK variants found in lung cancer revealed differences in the variant’s function, localization, and sensitivity to HSP90 inhibitors in clinical use [6]. Additionally, for some fusions, subcellular localization controls fusion activation, as is the case for MSN-ALK which congregates at the plasma membrane [8]. While most ALK fusions appear pan-cytoplasmic, others like RANBP2-ALK (perinuclear) and NPM-ALK (nuclear, nucleolar, and cytoplasmic) have different localization, the effects of which have yet to be investigated [9]. Very little is known about how signaling downstream of an ALK fusion may differ from that of a ROS1 or RET fusion in lung cancer. In addition, how different gene fusion partners may affect downstream signaling from a specific kinase fusion also remains an open question. One provocative study of various ALK fusions found in anaplastic large cell lymphoma demonstrated that the fusions were differentially able to activate PI3K and JAK-STAT signaling [10]. Furthermore, the ability of the different ALK fusions to activate PI3K kinase activity correlated with the fusion’s transendothelial migration properties. Overall, this study supports the hypothesis that the specific fusion gene partner defines the activity, signaling specificity, and phenotypic properties of the kinase fusion. Notably, the most commonly employed clinical diagnostics used to detect kinase fusions, including immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), will not specify which fusion partner is present within a tumor. However, as more sophisticated next-generation sequencing technologies come to the forefront of clinical diagnostics, clinicians will not only know that a tyrosine kinase fusion is present, but also to which specific gene partner the kinase is fused At present, there is very little data, all retrospective, to address the question of how a different fusion partner may affect clinical outcomes and disease responsiveness to targeted therapies. This is largely because the trials have used methods, such as IHC and FISH, to define eligibility criteria. In-depth contextual studies in pre-clinical models of lung cancer and in clinical trials in patients with kinase fusion positive disease are lacking; however, further analysis of this issue will allow us to refine the treatment of fusion positive lung cancer on a more personalized level in order to more effectively inhibit tumor growth and understand potential therapeutic resistance mechanisms. References 1. Kwak, E.L., et al., Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med, 2010. 363(18): p. 1693-703. 2. Shaw, A.T., et al., Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med, 2014. 371(21): p. 1963-71. 3. Drilon, A., et al., Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov, 2013. 3(6): p. 630-5. 4. Vaishnavi, A., et al., Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer. Nat Med, 2013. 19(11): p. 1469-72. 5. Soda, M., et al., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature, 2007. 448(7153): p. 561-6. 6. Richards, M.W., et al., Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain. Biochem J, 2015. 467(3): p. 529-36. 7. Zhao, X., et al., Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat Struct Biol, 2002. 9(2): p. 117-20. 8. Tort, F., et al., Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab Invest, 2001. 81(3): p. 419-26. 9. Chiarle, R., et al., The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer, 2008. 8(1): p. 11-23. 10. Armstrong, F., et al., Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells. Oncogene, 2004. 23(36): p. 6071-82.

      Table 1: Spectrum of tyrosine kinase fusions detected to date in NSCLC
      Kinase Gene Fusion partner
      ALK EML4
      KIF5B
      KLC1
      PTPN3
      SQSTM1
      STRN
      TFG
      NTRK1 CD74
      MPRIP
      ROS1 CCDC6
      CD74
      CLTC
      EZR
      FIG
      GOPC
      LIMA
      LRIG3
      MSN
      SDC4
      SLC34A2
      TPM3
      RET CCDC6
      CUX1
      KIAA1468
      KIF5B
      NCOA
      TRIM33


      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.