PI3K/AKT Pathway and Therapeutic Resistance

Preclinical data suggest that the PI3K/AKT pathway may be upregulated as a result of targeting other signaling pathways.1-3

  • The PI3K/AKT pathway has been implicated as a key player in the development of resistance to endocrine therapy1
  • The activation of the PI3K/AKT pathway has been implicated in de novo and acquired treatment resistance to targeted therapies in multiple tumor types1
  • Repression of the androgen receptor in prostate cancer was shown in preclinical models to induce AKT activity, indicating the existence of a reciprocal feedback mechanism2,3
  • It has been reported that many tumors upregulate AKT in order to acquire resistance to standard chemotherapies and targeted therapies 4
  • Inhibition of mammalian target of rapamycin complex (mTORC) 1 resulted in the upregulation of the AKT pathway, indicating the existence of a feedback loop 5

Approaches that include targeting the PI3K/AKT pathway in combination with other treatment modalities may be viable strategies to address resistance mechanisms. 1-3


  1. LoRusso PM. J Clin Oncol. 2016;34:3803-3815. PMID: 27621407
  2. Statz CM, Patterson SE, Mockus SM. Targ Oncol. 2017;12:47-59. PMID: 27503005
  3. Bitting RL, Armstrong AJ. Endocr Relat Cancer. 2013;20:R83-R99. PMID: 23456430
  4. Huang WC, Hung MC. J Formos Med Assoc. 2009;108:180-194. PMID: 19293033
  5. Gupta M, Hendrickson AEW, Yun SS, et al. Blood. 2012;119:476-487. PMID: 22080480