CDK 4/6 Inhibition Overcomes Acquired and Inherent Resistance to PI3Kα Inhibition in Pre-Clinical Models of Head and Neck Squamous Cell Carcinoma

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.

Configurational Assignment of a Flexible Benzo[g]isochromene Stereodiad from Rubia philippinensis and Inhibition of Soluble Epoxide Hydrolase Activity

“…Rubia philippinensis Elmer (Rubiaceae) is a rambling and low-climbing perennial plant and has rarely been investigated for its diverse chemical constituents and biological activities until the past decade. − In a continuing initiative for the identification of bioactive secondary metabolites from R. philippinensis , we herein applied combinatorial applications of contemporary NMR-coupled computational protocols to elucidate the full structure of the new benzo­[ g ]­isochromene 1 bearing a flexible stereodiad, identified from the title plant. The configurational analysis was implemented via computational approaches such as DP4, direct J -DP4 (d J -DP4), and DP4 Plus with shielding tensors and coupling constants considered.…”

IGF2 Mediates Resistance to Isoform-Selective-Inhibitors of the PI3K in HPV Positive Head and Neck Cancer

“…Different molecular paths can lead to isiPI3K resistance, including sustained activation of mTORC1 [ 21 , 54 , 55 ], PDK1/SGK1 [ 56 ], and MYC [ 57 ]. In HNC HPV− , acquisition of resistance to isiPI3K is driven by increased activity of receptor tyrosine kinases (RTK), like EGFR [ 20 , 58 ], AXL [ 20 , 59 , 60 ], and HER3 [ 61 ], which signal through AKT or RAS/ERK pathways, or by activation of RTKs downstream of ERK/TSC2 [ 61 ], p85 [ 62 ], and CDK4/6 [ 63 ]. While, in HNC HPV− , different mechanisms of resistance to isiPI3K have been well documented by us and by others, in HNC HPV+ , only innate resistance to isiPI3K has been reported [ 64 ].…”

Organoids and Liquid Biopsy in Oral Cancer Research

“…In accordance with excessive CDKs in HNSCC disclosed by the genomic studies, Remer et al reported that CDK4/6 inhibitors are effective to overcome acquired, inherent resistance to PI3Kα inhibition in pre-clinical models of HNSCC [ 27 ]. Besides, a CDK2 inhibitor could be another approach to target cancer drug resistance [ 12 ].…”