Author of

• 11372

  +

  O08 - Preclinical Therapeutic Models I (ID 92)

  • Event: WCLC 2013
  • Type: Oral Abstract Session
  • Track: Biology
  • Presentations: 1
  • Moderators:C. Mascaux, R. Natale
  • Coordinates: 10/28/2013, 16:15 - 17:45, Bayside Auditorium A, Level 1

  • 11377

    +

    O08.06 - Combining the HSP90 inhibitor, AT13387, with crizotinib improves response in an ALK-positive model of NSCLC. (ID 2163)

    17:00 - 17:10  |  Author(s): A. Rodriguez-Lopez
    • Abstract
    • Presentation
    • Slides

    Background
    Activation of anaplastic lymphoma kinase (ALK) via the EML4 translocation occurs in a proportion of non-small cell lung cancers (NSCLC). Whilst inhibitors of ALK such as crizotinib have been successful in the clinic, most patients ultimately relapse due to resistance via a number of different mechanisms. EML4-ALK and many critical components of signalling pathways involved in resistance are clients for the chaperone HSP90. This offers an alternative approach for targeting both ALK inhibitor-sensitive and -resistant disease through inhibition of HSP90 alone or in combination with an ALK inhibitor. AT13387 is a potent second-generation HSP90 inhibitor currently being clinically tested in a number of indications, including ALK-positive NSCLC as single-agent and in combination with the ALK inhibitor, crizotinib. Here we describe its activity in preclinical models of ALK-positive NSCLC and investigate its potential in combination with crizotinib.

    Methods
    The activity of AT13387 was investigated in vitro in the EML4-ALK translocated H2228 cell line. Protein levels were determined by western blotting. In vivo, AT13387 was evaluated in an H2228 tumor xenograft and an EML4-ALK translocated patient-derived xenograft model by measuring inhibition of tumor growth.

    Results
    AT13387 potently inhibited the proliferation of the crizotinib-sensitive EML4-ALK NSCLC cell line, H2228, in vitro with an IC~50~ value of 69 nM. The HSP90 client proteins, EML4-ALK and AKT, along with their phospho-forms, were depleted on treatment of these cells with AT13387. A simultaneous reduction in levels of phospho-ERK, phospho-AKT and phospho-S6 indicated that ALK signalling was inhibited, whilst induction of HSP70 confirmed HSP90 inhibition. In vivo, AT13387 demonstrated activity in ALK-dependent xenograft models, including an ALK-dependent patient-derived xenograft model. When mice bearing H2228 tumor xenografts were treated with AT13387 (70 mg/kg or 55 mg/kg ip once weekly), significant inhibition of tumor growth was observed. As expected, treatment with crizotinib (50 mg/kg po daily) caused partial tumor regression in this model (75% regression after 8 weeks of treatment). However, when AT13387 (55mg/kg weekly) was combined with the crizotinib treatment, a further enhancement of the inhibition of tumor growth over either of the monotherapies (88 % regression after 8 weeks) was observed, with 5 out of 7 tumors achieving complete regression, suggesting that the upfront addition of AT13387 to crizotinib treatment could lead to an improved response and potentially delay the emergence of resistance. In addition, this combination was well-tolerated.

    Conclusion
    AT13387 was shown to be effective in models of ALK-positive NSCLC as monotherapy or in combination with crizotinib, supporting the ongoing Phase II trial of AT13387 in ALK-positive NSCLC as single agent and in combination with crizotinib. These data suggest that treatment with an HSP90 inhibitor such as AT13387, alone or in combination with crizotinib, has therapeutic potential in ALK-positive NSCLC and that, furthermore, upfront combination of the two agents could extend the duration of response.

    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.

    Only Active 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 or select "Add to Cart" and proceed to checkout.