KIT and PDGFRA in Gastrointestinal Stromal Tumours

Two Mutually Exclusive Drivers

About 75 to 80 percent of gastrointestinal stromal tumours have an activating KIT mutation, and around 10 percent have an activating PDGFRA mutation. The two are essentially never found together, since both activate the same downstream signalling.

The remaining tumours, historically called wild-type GIST, are driven by other mechanisms such as SDH deficiency, NF1 loss, or BRAF mutation, and behave differently.

Why the Exon Matters

KIT exon 11 mutations (juxtamembrane domain) are the most common and respond best to standard-dose imatinib. KIT exon 9 mutations (extracellular domain), typical of small-bowel GIST, respond better to a higher imatinib dose.

The PDGFRA D842V mutation in exon 18 is primarily resistant to imatinib and to most other tyrosine-kinase inhibitors, but responds to avapritinib, which was developed specifically for it. Identifying it before treatment avoids an ineffective first-line drug.

The Line of Therapy Sequence

Imatinib is first-line for most KIT-mutant GIST. On progression, sunitinib and then regorafenib are used, and ripretinib is approved for later lines. Each has a different profile of coverage against secondary mutations.

Adjuvant imatinib after surgery is guided by risk of recurrence and by mutation status, since imatinib-insensitive genotypes gain little from it.

Acquired Resistance

Resistance to imatinib usually develops through secondary KIT mutations in the ATP-binding pocket (exons 13 and 14) or the activation loop (exons 17 and 18). Different subsequent drugs cover different secondary mutations, and a single tumour can harbour several resistant subclones in different lesions.

This heterogeneity is one reason later-line drugs with broad secondary-mutation coverage, and re-biopsy or circulating tumour DNA at progression, are useful.

Interpretation Notes

Mutational testing is recommended for essentially all GIST before systemic therapy, because genotype changes both drug choice and dose.

A KIT immunohistochemistry (CD117) positive result supports the diagnosis but does not identify the mutation or its exon, which requires sequencing.

Key Takeaways

• ·Most GIST is driven by a mutually exclusive activating mutation in KIT or PDGFRA.
• ·KIT exon 11 responds well to standard imatinib; exon 9 needs a higher dose.
• ·PDGFRA D842V resists imatinib but responds to avapritinib, so it must be identified first.
• ·Acquired resistance is via secondary KIT mutations, often heterogeneous between lesions.