Gastrointestinal stromal tumors (GISTs) are predominantly initiated by KIT mutations. In this study, we observed that discoidin domain receptors 1 and 2 (DDR1 and DDR2) exhibited high expression in GISTs, were associated with KIT, and enhanced the activation of both wild-type KIT and primary KIT mutants. Inhibition of DDR1/2 led to a reduction in the activation of KIT and its downstream signaling molecules, ultimately impairing GIST cell survival and proliferation in vitro. Consequently, treatment of mice carrying germline KIT/V558A mutation with DDR1/2 inhibitor significantly impeded tumor growth, and the combined use of DDR1/2 inhibitor and imatinib, the first-line targeted therapeutic agent for GISTs, markedly enhanced tumor growth suppression. In addition, DDR1/2 inhibition resulted in decreased KIT expression, while KIT inhibition led to upregulation of DDR1/2 expression in GISTs. The presence of DDR1/2 also decreased the sensitivity of wild-type KIT or primary KIT mutants to imatinib, indicating a possible role for DDR1/2 in promoting GIST survival during KIT-targeted therapy. The development of drug-resistant secondary KIT mutations is a primary factor contributing to GIST recurrence following targeted therapy. Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.
Keywords: DDR; GIST; KIT; imatinib; mutation.
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