AXL overexpression is a common resistance mechanism to anticancer therapies, including the resistance to BYL719 (Alpelisib) — the p110α isoform specific inhibitor of phosphoinositide 3-kinase (PI3K) — in esophagus squamous cell carcinoma (ESCC) and head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying AXL overexpression in resistance to BYL719 remain elusive. Here, we demonstrate that the AP-1 transcription factors c-JUN and c-FOS regulate AXL overexpression in HNSCC and ESCC. The expression of AXL was correlated with that of c-JUN both in HNSCC patients and in HNSCC and ESCC cell lines. Silencing of c-JUN and c-FOS expression in tumor cells downregulated AXL expression and enhanced the sensitivity of human papilloma virus–positive (HPVPos) and –negative (HPVNeg) tumor cells to BYL719 in vitro. Blocking of JNK using SP600125 in combination with BYL719 showed a synergistic antiproliferative effect in vitro, which was accompanied by AXL downregulation and potent inhibition of the mTOR pathway. In vivo, the BYL719–SP600125 drug combination led to the arrest of tumor growth in cell line–derived and patient-derived xenograft models, as well as in syngeneic head and neck murine cancer models. Collectively, our data suggest that JNK inhibition, in combination with anti-PI3K therapy, is a new therapeutic strategy that should be tested in HPVPos and HPVNeg HNSCC and ESCC patients.
Mai Badarni, Manu Prasad, Noa Balaban, Jonathan Zorea, Ksenia M. Yegodayev, Ben-Zion Joshua, Anat Bahat Dinur, Reidar Grénman, Barak Rotblat, Limor Cohen, Moshe Elkabets
Usage data is cumulative from April 2023 through April 2024.
Usage | JCI | PMC |
---|---|---|
Text version | 679 | 302 |
53 | 49 | |
Figure | 216 | 0 |
Supplemental data | 46 | 14 |
Citation downloads | 18 | 0 |
Totals | 1,012 | 365 |
Total Views | 1,377 |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.