PDGFRA-mutated GIST

The therapy for gastrointestinal stromal tumors (GISTs) has been revolutionized by tyrosin kinase inhibitors.

Clinicopathologic studies have been conducted to assess therapeutical responses in cases with KIT and platelet-derived growth factor receptor α (PDGFRA) gene mutations.

Cell culture data suggest that Akt/mammalian target of rapamycin (mTOR) kinase signaling may be important in GIST. (21326036)

The activation of the mTOR pathway is not a general hallmark of GIST with KIT mutations. However, mTOR signaling seems to be activated in PDGFRA mutants and in wild-type cases, which suggests that mTOR or upstream mTOR inhibitors may be therapeutically useful in primary resistant GISTs and confirms earlier data that mTOR is a crucial survival pathway in resistant GISTs. (21326036)

Examples

 PDGFRA-exon 18 mutations

• In vitro studies suggested increase sensitivity to imatinib; however, too few patients have been included in clinical trials to have an accurate understanding of their response to treatment.
• Although exon specific data have not been provided, adjuvant imatinib significantly improves relapse free survival for patients with non-D842V PDGFRA-mutated GIST (Corless et al. 2010), although survival was unaffected by adjuvant treatment.
• There are no specific data on the potential benefit of 3 years adjuvant imatinib vs 1 year imatinib for patients with PDGFRA mutations; these data are immature (Joensuu et al. 2011).
• https://www.mycancergenome.org/content/disease/gist/pdgfra/53/

 PDGFRA-D842V

• The D842V mutation results in an amino acid substitution at position 842 in PDGFRA, from an aspartic acid (D) to a valine (V). This mutation occurs within the TK2 domain.
• PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach.
• The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance.
• Few patients with D842V mutated GISTs experienced a recurrence in the one-year imatinib adjuvant study.
• Thus, adjuvant imatinib had no impact on relapse-free survival (Corless et al. 2010), although survival was unaffected by adjuvant treatment.
• There are no specific data on the potential benefit of 3 years adjuvant imatinib vs 1 year imatinib for patients with PDGFRA mutations; these data are immature (Joensuu et al. 2011).
• https://www.mycancergenome.org/content/disease/gist/pdgfra/45/

References

 The activated targets of mTOR signaling pathway are characteristic for PDGFRA mutant and wild-type rather than KIT mutant GISTs. Sápi Z, Füle T, Hajdu M, Matolcsy A, Moskovszky L, Márk A, Sebestyén A, Bodoky G. Diagn Mol Pathol. 2011 Mar;20(1):22-33. PMID: 21326036