dovitinib

Overview

Dovitinib (TKI258) is a multi-targeted kinase inhibitor active against FGFR1/2/3, VEGFR1/2/3, PDGFR, KIT, FLT3, and CSF1R. It was investigated in clinical trials for renal cell carcinoma and other solid tumors but did not achieve regulatory approval. In the UCLA sarcoma PDTO screen it was tested in the >400-compound panel and showed subtype-specific differential sensitivity.

Evidence in the corpus

  • In the UCLA sarcoma PDTO biobank (sarcoma_ucla_2024, n=194 specimens), leiomyosarcoma PDTOs were more sensitive to dovitinib (p=0.0068) compared to the pan-sarcoma average, consistent with prior negative trials in LMS with less selective agents. PMID:39305899
  • In patient SARC0133 (RMS) who harbored an FGFR1 gain on chromosome 8, the PDTO was a top responder to infigratinib (an FGFR-selective inhibitor) but showed minimal response to dovitinib, demonstrating intra-class drug differentiation within FGFR inhibitors. PMID:39305899
  • Three likely activating FGFR2 mutations identified in adenoid cystic carcinoma (ACYC) prompted nomination of FGFR inhibitors including dovitinib (NCT01524692 trial) as a therapeutic strategy in this disease PMID:23778141.

Resistance mechanisms

  • FGFR1 genomic gain (chromosome 8) does not predict sensitivity to dovitinib in sarcoma, despite predicting sensitivity to the more selective FGFR inhibitor infigratinib — illustrating that multi-kinase inhibitor promiscuity may dilute on-target efficacy. PMID:39305899

Cancer types (linked)

  • LMS — leiomyosarcoma; significantly more sensitive to dovitinib than pan-sarcoma average (p=0.0068).
  • RMS — rhabdomyosarcoma; SARC0133 FGFR1-gain specimen resistant to dovitinib despite infigratinib sensitivity.

Sources

  • PMID:39305899 — Al Shihabi et al. (Cell Stem Cell 2024). UCLA sarcoma PDTO biobank; dovitinib LMS sensitivity signal; dovitinib vs infigratinib intra-class differentiation in FGFR1-gain RMS.
  • PMID:23778141 — Stephens et al. (2013). Whole-exome sequencing of 24 adenoid cystic carcinoma tumors; activating FGFR2 mutations nominate FGFR inhibitors including dovitinib as a therapeutic strategy.

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