AKT-independent signaling in PIK3CA-mutant thyroid cancer mediates resistance to dual SRC and MEK1/2 inhibition

Med Oncol. 2023 Sep 15;40(10):299. doi: 10.1007/s12032-023-02118-2.


Anaplastic thyroid cancer (ATC) is a rare and aggressive disease with 90% of patients succumbing to this disease 1 year after diagnosis. The approval of the combination therapy of a BRAF inhibitor dabrafenib with the MEK1/2 inhibitor trametinib has improved the overall survival of ATC patients. However, resistance to therapy remains a major problem. We have previously demonstrated combined inhibition of Src with dasatinib and MEK1/2 with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells, however PIK3CA-mutant cells exhibit a mixed response. Herein, we determined that AKT is not a major mediator of sensitivity and instead PIK3CA-mutants that are resistant to combined dasatinib and trametinib have sustained activation of PDK1 signaling. Furthermore, combined inhibition of PDK1 and MEK1/2 was sufficient to reduce cell viability. These data indicate PDK1 inhibition is a therapeutic option for PIK3CA mutations that do not respond to combined Src and MEK1/2 inhibition.

Keywords: Dasatinib; MAPK; PI3K; Src; Thyroid cancer; Trametinib.

MeSH terms

  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Dasatinib / pharmacology
  • Humans
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • Thyroid Carcinoma, Anaplastic* / drug therapy
  • Thyroid Carcinoma, Anaplastic* / genetics
  • Thyroid Neoplasms* / drug therapy
  • Thyroid Neoplasms* / genetics


  • Proto-Oncogene Proteins c-akt
  • Dasatinib
  • Proto-Oncogene Proteins B-raf
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human