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SHP2 Inhibition Influences Therapeutic Response to Tepotinib in Tumors with MET Alterations

Linda Pudelko1, Frank Jaehrling1, Christof Reusch1

  • 1Translational Innovation Platform Oncology, Merck KGaA, Darmstadt 64293, Germany.

Iscience
|December 11, 2020
PubMed

Insights

Tepotinib treats non-small cell lung cancer (NSCLC) with METex14 mutations. Combining tepotinib with an SHP2 inhibitor overcomes resistance and improves tumor control in MET-altered lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Tepotinib is an approved oral MET inhibitor for metastatic non-small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping mutations.
  • Understanding resistance mechanisms to tepotinib is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate co-occurring receptor tyrosine kinases (RTKs) in MET-altered NSCLC.
  • To evaluate the efficacy of combining tepotinib with an SHP2 inhibitor to overcome resistance.

Main Methods:

  • Analysis of treatment-naive and tepotinib-resistant cells with MET amplification or METex14 skipping mutations.
  • Examination of RTK co-existence and gene copy number gains in a patient cohort.
  • In vitro and in vivo studies evaluating tepotinib combined with an SHP2 inhibitor.

Main Results:

  • Other RTKs co-exist with MET alterations and become prominent upon tepotinib resistance.
  • Gene copy number gains of RTKs at baseline correlated with treatment outcomes in patients.
  • SHP2 inhibition delayed tepotinib resistance and synergized with tepotinib in various models.

Conclusions:

  • Alternative signaling pathways contribute to tepotinib resistance in MET-altered NSCLC.
  • Combination therapy with tepotinib and an SHP2 inhibitor demonstrates potential for enhanced tumor growth control.
Keywords:
CancerTreatment

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