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J. Jean Cui



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.09 - ALK/ROS1/TRK Inhibitor TPX-0005 Effectively Overcomes Clinical Resistance Solvent Front Mutations (ID 8467)

      15:45 - 17:30  |  Presenting Author(s): J. Jean Cui

      • Abstract
      • Presentation
      • Slides

      Background:
      ALK, ROS1 and TRK kinase inhibitors have achieved tremendous success in the treatment of lung cancer patients with abnormal ALK, ROS1 or NTRK gene. However, the emergence of drug resistance limits their long term clinical applications. An ever increasing number of acquired resistance mutations are being reported from the clinic. In addition to the gatekeeper mutations, the solvent front mutations have been recently recognized as common resistance mutations to many kinase inhibitors. For example, the solvent front ALK G1202R mutant conferred resistance to many clinical ALK inhibitors in lung cancer including crizotinib, ceritinib, alectinib, and brigatinib. The same position mutations ROS1 G2032R, TRKA G595R and TRKC G623R rendered resistance to the ROS1 inhibitor crizotinib in lung cancer, pan-TRK inhibitor entrectinib and larotrectinib in colon cancer, and larotrectinib in infantile fibrosarcoma, respectively.

      Method:
      A conserved glycine residue at the hinge C-terminal forms a hydrophobic sandwich with the kinase beta 1 sheet. Kinase inhibitors often use an aromatic ring or a flat motif to fit through this narrow glycine sandwich to the solvent. Alterations at the conserved glycine or the nearby residues, commonly referred to as solvent-front mutations, clash with the inhibitor motif and induce clinical resistance. Here, we designed TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ALK, ROS1, and TRK inhibitors in the clinic to avoid the steric clash inside the sandwich.

      Result:
      TPX-0005 resides at the center of the highly conserved ATP site without direct contact with the solvent front glycine sandwich. As expected, TPX-0005 potently inhibited WT EML4-ALK and solvent front mutant EML4-ALK G1202R with similar activities in both enzymatic (WT Ki 0.87 nM vs G1202R 0.81 nM) and Ba/F3 cell proliferation assays (WT IC~50~ 21.1 nM vs G1202R 20.5 nM). TPX-0005 showed potent activities against CD74-ROS1 G2032R (IC~50~ 8.4 nM), LMNA-TRKA G595R (IC~50~ 0.4 nM), TEL-TRKB G639R (IC~50~ 1.9 nM) and TEL-TRKC G623R (IC~50~ 0.4 nM) in Ba/F3 cell proliferation assays. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor growth inhibition and tumor regression in the tumors carrying WT and solvent-front mutations of ALK, ROS1 or TRKA fusion genes, respectively.

      Conclusion:
      Taken together, preclinical results demonstrated that TPX-0005 is a novel ALK/ROS1/TRK inhibitor overcoming the profound solvent front kinase mutations. TPX-0005 will bring new methods for the treatment of resistance patients with solvent front mutations in ALK, ROS1, or TRK fusion genes. A phase 1/2 study of TPX-0005 in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1) is actively pursued (NCT03093116).

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-073 - TPX-0005 with an EGFR Tyrosine Kinase Inhibitor (TKI) Overcomes Innate Resistance in EGFR Mutant NSCLC (ID 8956)

      09:30 - 16:00  |  Author(s): J. Jean Cui

      • Abstract
      • Slides

      Background:
      Overexpression of several receptor tyrosine kinases (RTKs) substitutes EGFR signaling in EGFR-mutant NSCLC. The MET ligand hepatocyte growth factor (HGF) provides an alternative signaling mechanism for EGFR by inducing inter-receptor cross talk with EphA2, CUB domain-containing protein-1 (CDCP1) or AXL. SHP2, a non-receptor protein tyrosine phosphatase is central in signal transduction downstream of RTK signaling and in Src activation. We previously demonstrated that STAT3 and Src-YAP1 signaling limits EGFR TKI efficacy in EGFR-mutant NSCLC. We are now exploring the possibility of multiple RTK activation through a Src-YAP1-mediated transcriptional program. We are evaluating whether combined EGFR inhibition with TPX-0005, a novel orally available multikinase inhibitor and potent Src/FAK and JAK2 inhibitor, can be more efficient than EGFR inhibition alone in EGFR-mutant NSCLC cells.

      Method:
      We studied the mRNA expression levels of stromal HGF and tumor RTKs, AXL, CDCP1, MET, and EphA2, as well as SHP2, and clinical outcome in baseline samples of 64 EGFR-mutant NSCLC patients treated with first-line EGFR TKI. We combined in vitro approaches to explore whether gefitinib or osimertinib combined with TPX-0005 can abolish STAT3 and Src-YAP1 and downregulate the expression of RTKs.

      Result:
      High levels of AXL, CDCP1 and SHP2 mRNA expression were associated with worse outcome to EGFR TKI in 64 EGFR-mutant NSCLC patients. Median progression-free survival (PFS) was 14.5 and 23.4 months for patients with high and low AXL mRNA, respectively (p=0.0359). Median PFS was 9.1 and 20.2 months for patients with high and low CDCP1 mRNA, respectively (p=0.0179). Tumoral EPHA2 and MET or stromal HGF levels did not affect PFS. Median PFS was 11.4 and 24.1 months for patients with high and low SHP2 mRNA, respectively (p=0.0094). The combination of gefitinib/osimertinib with TPX-0005 resulted in highly synergistic suppression of cell viability and reduced colony formation in two EGFR-mutant cell lines. The combination abolished the EGFR inhibition-induced STAT3 and YAP1 phosphorylation, as confirmed by western blotting and immunofluorescence. The results of TaqMan quantitative-PCR assay revealed that gefitinib/osimertinib plus TPX-0005 reduced the mRNA levels of AXL, CDCP1 and MET, an effect that could not be obtained with EGFR inhibition alone. In vivo experiments are ongoing.

      Conclusion:
      AXL and CDCP1 are adverse predictive markers of PFS in EGFR-mutant NSCLC patients. STAT3 and Src-YAP1 signaling limits the efficacy EGFR TKI. Combined EGFR inhibition with TPX-0005 (currently in phase I clinical testing) is a particularly attractive strategy

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