Kinaddict · Vulnerability of esophageal cancer to their addiction to kinase activities: evaluation and prediction of eSCC tumors responsiveness to kinase inhibitors.

Vulnerability of esophageal cancer to their addiction to kinase activities: evaluation and prediction of eSCC tumors responsiveness to kinase inhibitors.

Esophageal cancer (EC) ranks amongst the deadliest cancers worldwide with a 5-year survival ranging around 20%, that barely improved over the past two decades. The standard of care of the main EC disease, the squamous cell carcinoma (eSCC), consisting of surgery with neo-/adjuvant treatment combined or not with mitotic poisons has shown poor efficacy as such patients develop recurrences, causing death in a year. In this context, a deeper understanding of the pathogenesis is required to improve the treatment offered to patients with EC. Genomics analyses have pictured over the years a broad heterogenic genetic landscape between individuals with EC as well as inter- and intra-tumors, hampering in fine the approval of alternative treatments against EC. Reports of genomic alterations revealed the high prevalence of aberrations affecting the cell cycle regulation, especially on the Cyclin D - CDK4 – pRB – E2F axis in addition of other cascades originating from mutations and amplifications of RTKs (receptor tyrosine kinases), downstream mediators, or regulators of the oxidative stress, squamous cell differentiation, and WNT-ß Catenin signaling. To evaluate alternative therapies, the project aimed to identify kinase and their activity to which EC is addicted and use the broad arsenal of small inhibitor molecules to target specific kinases. By their critical role in the cell cycle progression, CDK1/2/4/7 are undeniably good target choices but only the inhibition of CDK4 (together with related CDK6) has been recently successful in cancer targeted therapy, due to its major effects on progression-free survival without major side effects. The understanding of the cell circuitry especially at kinase level and their associated pathways is necessary to determine the vulnerabilities of each tumor and propose an optimized treatment modality. In this idea, the present project aimed to define the activity of protein kinases in eSCC tumor cells alongside genetic alterations, and identify kinases to which tumor cells are addicted to. Because of the high probability of response of eSCC tumors to CDK4i, the verification of response of eSCC tumors cells to CDK4i is followed by the molecular analysis of potential acquired resistance and the assessment of combined therapies with CDK4i to identify biochemical markers predicting the response. Such novel therapies, although such would lead to significant benefits for many patients, are not deprived of flaws as it would not be the case for other patients. Furthermore, the cost of treatment using such novel drugs have shown to be a burden for patients and public health care systems. It pushes the need to deeper characterize the tumors from each patient and stratify those that would benefit of such targeted therapies.

Data: CORDIS, © European Union