What is the role of receptor tyrosine kinases (RTKs) in cancer treatment?

Receptor Tyrosine Kinases in Cancer Treatment: Targeting TRK Fusions

Receptor tyrosine kinases (RTKs) play a critical role in cancer treatment through targeted inhibition of oncogenic fusion proteins, particularly TRK fusions, which have demonstrated remarkable 75% response rates across multiple tumor types regardless of histology. 1

Mechanism and Function of RTKs in Normal Physiology

RTKs are transmembrane receptors that regulate critical cellular processes:

• The TRK-receptor family includes TRKA, TRKB, and TRKC (encoded by NTRK1, NTRK2, and NTRK3 genes)
• In normal cells, TRK receptors:
  • Dimerize after ligand binding
  • Become catalytically active through tyrosine phosphorylation
  • Signal through multiple pathways including PI3K, phospholipase C-γ, and MAP kinase pathways 1
• Normal functions include regulation of embryonic growth, differentiation, and neuronal survival
• Postnatally, TRK receptors have limited functions in pain sensation, mood regulation, and proprioception 1

Oncogenic Mechanisms of RTKs

RTKs become oncogenic through several mechanisms:

• Chromosomal translocations/fusions: Most common and clinically actionable
  • 5' region of a gene fuses with 3' region of NTRK gene
  • Results in constitutive activation of TRK kinase without ligand binding
  • Drives downstream signaling through PI3K and MAP kinase pathways 1
• Other mechanisms (less clinically relevant for targeted therapy):
  • Gene mutations
  • Splice variants
  • Amplifications
  • Autocrine activation 2

TRK Fusions in Cancer

TRK fusions have a distinct pattern of occurrence:

• High-frequency tumor types (almost universal presence):

  • Infantile fibrosarcoma
  • Cellular congenital mesoblastic nephroma
  • Secretory breast cancer
  • Mammary analog secretory carcinoma 1

• Lower-frequency tumor types:

  • Undifferentiated sarcomas
  • Gliomas
  • Papillary thyroid cancers
  • Spitzoid neoplasms
  • Inflammatory myofibroblastic tumors
  • Acute leukemias
  • Lung cancer (0.1-0.3% overall, but enriched 10-fold in tumors without other oncogenic drivers) 1

• Mutual exclusivity: TRK fusions are typically mutually exclusive with other strong oncogenic drivers like KRAS, BRAF, NRAS, and EGFR mutations 1

Therapeutic Targeting of RTKs in Cancer

The identification of RTK alterations has led to targeted therapies:

• TRK inhibitors: FDA-approved with tumor-agnostic indications

  • Larotrectinib and entrectinib demonstrated high response rates in TRK fusion-positive tumors
  • Approved for patients with:
    • NTRK fusion without acquired resistance mutations
    • Metastatic or unresectable disease
    • Progression on prior therapy or no satisfactory alternative treatment 1

• Other RTK inhibitors: Target-specific RTKs in specific contexts

  • Example: Gefitinib targets EGFR in non-small cell lung cancer with specific EGFR mutations (exon 19 deletions or exon 21 L858R substitutions) 3

Testing for TRK Fusions

Identifying patients who may benefit from TRK inhibitors requires appropriate testing:

• For tumors likely to harbor TRK fusions:

  • Immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) 1

• For tumors with lower prevalence of TRK fusions:

  • Next-generation sequencing (NGS), preferably RNA-based 1
  • Helps identify both TRK fusions and other targetable oncogenic drivers

Clinical Implications and Future Directions

The understanding of RTKs in cancer has significant clinical implications:

• Histology-agnostic approach: TRK inhibitors work across tumor types based on the presence of NTRK fusions rather than tissue of origin 1

• Resistance mechanisms: Despite initial responses, resistance to TRK inhibitors can develop, necessitating ongoing research into next-generation inhibitors 4

• Combination approaches: Combining RTK inhibitors with other therapies (chemotherapy, immunotherapy, or multiple RTKIs) may overcome resistance 5

Pitfalls and Caveats

Important considerations when targeting RTKs in cancer:

• Not all RTK alterations are clinically actionable - only fusions have demonstrated consistent response to TRK inhibitors 1

• Testing methodology matters - RNA-based NGS is more sensitive for detecting gene fusions than DNA-based methods 1

• TRK inhibitors are indicated for patients with no satisfactory alternative treatments or progression on prior therapy 1

• Resistance can develop through acquired mutations in the TRK kinase domain, requiring different therapeutic approaches 1