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  • American Association for Cancer Research (AACR)  (2)
  • Medicine  (2)
  • 1
    Online Resource
    Online Resource
    Abstract 3182: Kindlin-1 expression is associated with EGFR/RAS/MAPK activation and response to MEK inhibitors in triple-negative breast cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3182-3182
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 3182-3182
    Abstract: Background: Triple-negative breast cancer (TNBC) accounts for ~15% of all invasive breast cancers. This heterogeneous group of tumors is the most aggressive and difficult-to-treat subtype of breast cancer. We previously demonstrated that Kindlin-1 is overexpressed in TNBC and patients with high Kindlin-1 have a worse prognosis. We determined that Kindlin-1 plays a major role in the epithelial to mesenchymal transition, tumor growth and breast cancer metastasis. TNBC have also been reported to express high levels of EGFR, in ~70% of the cases. Unfortunately, anti-EGFR therapy in TNBC fails to show a clinical benefit. In this study, we aimed to investigate a potential link between EGFR/RAS/MAPK pathway and Kindlin-1 in TNBC, and to propose new therapeutic strategies based on our findings. Methods: First, a gene set enrichment analysis was performed in 58 breast cancer cell lines (CCLE dataset) to detect the signaling pathways differentially enriched in cells expressing high levels of Kindlin-1. We next evaluated whether Kindlin-1 expression could be associated to an increased MAPK signaling by testing the mutational status and phosphorylation of key effectors of the pathway. To determine whether Kindlin-1 could be a predictive biomarker for the response to MEK inhibitors, we assessed its expression in sensitive versus resistant cell lines. Finally, we examined in vivo the anti-tumor efficacy of Selumetinib in a series of 27 triple negative breast cancer patient derived xenografts (PDX), highly representative of the originating tumor in terms of biology and therapeutic sensitivity. These PDX models have been characterized for Kindlin-1 expression (at RNA and protein levels). The sensitivity to MEKi of the TNBC PDX models was examined with regard to their Kindlin-1 expression. Results: Gene set enrichment analysis put in evidence that EGFR/RAS/MAPK pathway is upregulated in breast cancer cells with high Kindlin-1 expression. Although mutations are infrequent in breast cancer, an increased Kindlin-1 expression was observed in a subset of EGFR/RAS-activated cell lines (mutated or amplified). Moreover, TNBC expressing high levels of Kindlin-1 showed an increased phosphorylation of key effectors (ERK, MEK). We also demonstrated that Kindlin-1 mRNA expression was significantly increased in sensitive cell lines to different MEK inhibitors such as Trametinib (p=0.007) or Selumetinib (p=0.005) compared with resistant cells. In addition, in preclinical TNBC PDX models treated with Selumetinib there was a correlation between tumor growth inhibition and Kindlin-1 protein expression (r=0.57; p=0.017). Conclusion: Our findings indicate that Kindlin-1 expression may be a promising predictive biomarker of MEK inhibitors response in TNBC and may offer new therapeutic opportunities for patients with limited treatment options and refractory cancer types to current treatments. Citation Format: Paula Azorin, Florian Bonin, Zakia Tariq, Florence Coussy, Elisabetta Marangoni, Rosette Lidereau, Keltouma Driouch. Kindlin-1 expression is associated with EGFR/RAS/MAPK activation and response to MEK inhibitors in triple-negative breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3182.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-3182
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 1951: SMAC mimetic and BET inhibitor - a promising combination for solid cancer treatment
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1951-1951
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1951-1951
    Abstract: SMAC mimetics (SMACm), drugs that mimic natural antagonists of Inhibitor of Apoptosis (IAP) are in clinical trials for hematological malignancies and solid cancers. The clinical benefit for patients in monotherapy was so far dismal. Hence, current clinical evaluation of SMACm focuses on combinations, in particular with checkpoint inhibitors and/or radiation therapy. The BET family protein BRD4 is a “reader” of epigenetic information and binds to acetylated chromatin to act as a key regulator of transcription. BET inhibitors (BETi) were tested in numerous clinical trials as novel treatment option for hematological and solid cancers. Like SMACm, monotherapy with BETi showed only moderate clinical activity stressing the importance of combination trials. BI 891065 a monovalent, oral SMACm, with a favorable safety profile allowing continuous dosing, is in Clinical Phase I (NCT03166631, NCT04138823). BI 894999 is a very potent and selective oral BETi, administered by intermittent dosing in Clinical Phase I (NCT02516553). We studied the combinatorial effect of both compounds in vitro across a large number of human tumor cell lines (lung, colorectal, pancreatic, and gastric cancer) in proliferation assays using Bliss synergy analysis and IncuCyte ZOOM® live cell imaging, and in vivo in three independent models. Of the 60+ cancer cell lines, around 30% showed synergy when treated with the BI 891065 + BI 894999 combination, irrespective of indication. Efficacy correlated with downmodulation of the key apoptosis regulator XIAP by BI 894999. In most of the cell lines tested, the synergistic effect was blocked by addition of the TNFα scavenger Enbrel and/or the apoptotic pathway inhibitor zVAD. In vivo efficacy was tested in two PDAC xenograft models (one immunocompetent and one immunodeficient) and one CRC model at clinically relevant doses. Daily oral application of both compounds was well tolerated and did not lead to drug-drug interactions. Target engagement markers were modulated as expected (cIAP1 degradation for SMACm and Hexim1 induction for BETi) and not compromised by the combination. Tumor growth inhibition in the BxPC3 pancreas model achieved 22% TGI for 50 mg/kg BI 891065, 70% TGI for 2 mg/kg BI 894999, and 96% TGI for the combination. In the Pan02 pancreas model 9% TGI for 50 mg/kg BI 891065, 30% TGI for 4 mg/kg BI 894999 and 92% TGI for the combination were recorded. Evaluation of the cellular composition of the tumor microenvironment in this immunocompetent model showed distinct changes evident of a reduced immuno-suppressive milieu upon combination treatment. Combination effects on tumor growth in the CRC model LoVo were far less pronounced. These preclinical in vitro and in vivo data are highlighting the potential of a SMACm/BETi combination for the treatment of solid cancers. The identification of patient selection markers for this combination will be necessary for advancing this concept into pivotal clinical trials. Citation Format: Paula-Elena Traexler, Dominik Arnold, Florian Ebner, Ksenija Slavic-Obradovic, Robin Jacob, Ha Pham Thi Thanh, Martin Aichinger, Anke Baum, Andreas Wernitznig, Daniel Gerlach, Maria-Antonietta Impagnatiello, Valeria Santoro, Sabine Olt, Dirk Scharn, Regina Ruzicka, Reniqua P. House, Mary Y. Murphy, Ulrich Reiser, Harald Engelhardt, Vittoria Zinzalla, Thorsten Laux, Flavio Solca, Ulrike Tontsch-Grunt. SMAC mimetic and BET inhibitor - a promising combination for solid cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1951.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1951
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
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