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Common Co-activation of AXL and CDCP1 in EGFR-mutation-positive Non-smallcell Lung Cancer Associated With Poor

Niki Karachaliou1, Imane Chaib2, Andres Felipe Cardona3

  • 1Instituto Oncológico Dr Rosell (IOR), University Hospital Sagrat Cor, QuironSalud Group, Barcelona, Spain; Pangaea Oncology, Laboratory of Molecular Biology, Coyote Reserach Group, Quirón-Dexeus University Institute, Barcelona, Spain.

Ebiomedicine
|February 14, 2018
PubMed

Insights

CUB domain-containing protein-1 (CDCP1) and AXL expression predict resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). Combining EGFR TKIs with TPX-0005 may overcome this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epidermal growth factor receptor (EGFR)-mutation-positive non-small cell lung cancer (NSCLC) shows initial response to EGFR tyrosine kinase inhibitors (TKIs) but is ultimately incurable.
  • Innate resistance mechanisms to EGFR TKIs in NSCLC are not fully understood, hindering treatment efficacy.

Purpose of the Study:

  • To investigate receptor tyrosine kinases (RTKs), Src family kinases, and focal adhesion kinase (FAK) as genetic modifiers of innate resistance in EGFR-mutation-positive NSCLC.
  • To evaluate the efficacy of combining EGFR TKIs with a Src/FAK/Janus kinase 2 (JAK2) inhibitor, TPX0005, in preclinical models.

Main Methods:

  • Gene expression analysis was performed on two cohorts of EGFR-mutation-positive NSCLC patients treated with EGFR TKIs.
  • The efficacy of gefitinib or osimertinib combined with TPX0005 was evaluated in vitro and in vivo.
  • Prognostic significance of CUB domain-containing protein-1 (CDCP1) and the association of an AXL and CDCP1 expression model with clinical outcomes were assessed.

Main Results:

  • CDCP1 was identified as an independent negative prognostic factor for progression-free and overall survival in EGFR-mutation-positive NSCLC.
  • A two-gene model based on AXL and CDCP1 expression strongly correlated with clinical outcomes in both patient cohorts.
  • Combined treatment with EGFR TKI and TPX0005 suppressed RTK expression and activation, along with downstream signaling.

Conclusions:

  • Co-expression of CDCP1 and AXL contributes to innate resistance and limits the efficacy of EGFR TKIs in NSCLC.
  • Combined therapy with EGFR TKIs and TPX0005 demonstrates potential to overcome resistance and warrants further clinical investigation.
Keywords:
AXLCDCP1Combination therapiesEGFRLung cancerResistance

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