Pharmacologic profiling of eight anticancer agents in six HNSCC cell lines suggested that PIK3CA mutation may serve as a predictive biomarker for the drugs targeting the EGFR/PI3K pathway.
Tissue biopsies of 25 consecutive cases of HNSCC were tested for activating PIK3CA mutations at three mutational hotspots by real-time polymerase chain reaction.
We identified frequent PIK3CA mutations in patients with high-risk HNSCC confined predominantly to the oropharyngeal and sinonasal subsites; for the first time, mutation in AKT1 has been identified in HNSCC.
Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110α, in combination with radiation in HNSCC.
As such, current research aimed at elucidating the interactions between PI3K/Akt/mTOR and other important signaling pathways which may drive resistance in HNSCC, such as p53, NF-κB, and MAPK, has become a prominent focus toward better understanding how to most effectively treat HNSCC.
Here, we examined the responses of a large panel of patient-derived HNSCC cell lines to various combinations of PI3K and EGFR inhibitors, including EGFR agents with varying specificity and mechanistic characteristics.
Novel therapies under investigation in HNSCC include antibody and small molecule inhibitors of EGF receptor and its family members, PI3K inhibitors, antiangiogenic agents, immunotherapies and agents interacting with early developmental pathways such as Hedgehog.
HRAS mutant cells are resistant to PI3K inhibition and our findings suggest the involvement of a signalling intersection of the MAPK and PI3K pathways at the level of ERK-TSC2, leading to persistent mTOR activity. mTOR inhibition alone or in combination with MAPK pathway inhibition may be a promising therapeutic strategy for this subset of HNSCC tumors.
Emphasis is placed on the therapeutic implications of genes frequently altered in HNSCCs (i.e., TP53, PIK3CA, and NOTCH1) and their corresponding pathways, with a particular focus on recent findings of Notch signaling pathway activation in HNSCC.
Benign tonsils infected with high-risk HPV harbored mutations in EP300, NF1, PIK3CA, and RB1 which are considered relevant in the development of HPV-associated head and neck squamous cell carcinoma (SCC).
This study assessed the maximum tolerated dose (MTD) of the PI3K inhibitor buparlisib given concurrently with cetuximab in recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
The importance of PIK3CA alterations in squamous cell carcinoma of the head and neck (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA.
Combined treatment with cetuximab and MM-121 blocked EGFR and HER3 activities and inhibited the PI3K/AKT and ERK signaling pathways and HNSCC cell growth more effectively than each antibody alone.
Screening of PI3K pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib.
The poor prognostic value of GOF <i>TP53</i> variants and mTOR pathway upregulation was confirmed in the TCGA SCCHN cohort.<b>Conclusions:</b> Our study demonstrates a link of intratumoral heterogeneity and clonal evolution as important mechanisms of drug resistance in SCCHN and establishes mutant GOF <i>TP53</i> variants and the PI3K/mTOR pathway as molecular targets for treatment optimization.<i></i>.
BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, an FDA-approved radiosensitizing agent in the treatment of HNSCC.
The PI3K-AKT pathway is a downstream signaling pathway that has recently been found to play an important role in head and neck squamous cell carcinoma (HNSCC).