CDK 4/6 inhibition overcomes acquired and inherent resistance to pi3kα inhibition in pre‐clinical models of head and neck squamous cell carcinoma

Eric Remer, Mai Badarni, Elad Hikri, Avraham Dayan, Lirit Levi, Aron Popovtzer, Muhammed Iraqi, Angel Porgador, Ben Zion Joshua, Gideon Bachar, Moshe Elkabets, Maurizio Scaltriti, Aviram Mizrachi

Research output: Contribution to journalArticlepeer-review

Abstract

Activating alterations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide‐ 3‐kinase (PI3K), are prevalent in head and neck squamous cell carcinoma (HNSCC) and thought to be one of the main drivers of these tumors. However, early clinical trials on PI3K inhibitors (PI3Ki) have been disappointing due to the limited durability of the activity of these drugs. To investigate the resistance mechanisms to PI3Ki and attempt to overcome them, we conducted a molecular‐based study using both HNSCC cell lines and patient‐derived xenografts (PDXs). We sought to simulate and dissect the molecular pathways that come into play in PIK3CA‐altered HNSCC treated with isoform‐specific PI3Ki (BYL719, GDC0032). In vitro assays of cell viability and protein expression indicate that activation of the mTOR and cyclin D1 pathways is associated with resistance to PI3Ki. Specifically, in BYL719‐ resistant cells, BYL719 treatment did not induce pS6 and pRB inhibition as detected in BYL719‐sensitive cells. By combining PI3Ki with either mammalian target of rapamycin complex 1 (mTORC1) or cyclin D1 kinase (CDK) 4/6 specific inhibitors (RAD001 and abemaciclib, respectively), we were able to overcome the acquired resistance. Furthermore, we found that PI3Ki and CDK 4/6 inhibitors have a synergistic anti‐tumor effect when combined in human papillomavirus (HPV)‐negative/PIK3CA‐WT tumors. These findings provide a rationale for combining PI3Ki and CDK 4/6 inhibitors to enhance anti-tumor efficacy in HNSCC patients.

Original languageEnglish
Article number3214
Pages (from-to)1-12
Number of pages12
JournalJournal of Clinical Medicine
Volume9
Issue number10
DOIs
StatePublished - Oct 2020

Keywords

  • CDK 4/6
  • Head and neck squamous cell carcinoma
  • Human papillomavirus
  • MTOR
  • PI3K
  • PIK3CA

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