Focusing on a pivotal axis in chemoresistance

Chemotherapy is a frontline cancer treatment, but, over time, many cancers become resistant to the effects of chemotherapeutic drugs. Gastric carcinoma, or GC, is no exception and is among the top five causes of cancer-related mortalities worldwide. Chemoresistance occurs in GC via any number or combination of mechanisms, including a reduction in drug uptake or changes in the expression of molecular targets.

Marwah Al-Mathkour

Marwah Al-Mathkour, a postdoctoral fellow at the University of Miami, studies this problem. “I am working with my colleagues to define the signaling pathway that leads to drug resistance in gastric cancer,” she said. “One important player is the CDK1–SOX9 axis.” 

Cyclin-dependent kinase 1, or CDK1, is a critical cell cycle-regulating protein that shows increased tumor expression correlated with poor patient survival. The transcription factor SOX9 is a tumor suppressor in some cancers and an oncogene in others, including gastric cancer. CDK1 can regulate SOX9 expression through microRNA, or miRNA.

Al-Mathkour’s research in Wael El-Rifai’s lab focuses on underlying molecular and functional mechanisms of CDK1 and SOX9 genes in GC chemotherapy resistance. A challenging aspect of this work is trying to define how CDK1 and SOX9 drive this resistance. 

“We are trying different techniques to find the connection, to understand the epigenetic mechanisms that explain the relationship between CDK1 and SOX9,” Al-Mathkour said. “In my work, microRNA is one of the players that contribute to the drug resistance.” 

Researchers have previously reported specific miRNA changes in GC, which Al-Mathkour’s team observed in their data set. When they treated cells with a DNA methyltransferase inhibitor called 5-Aza, they saw upregulation in expression of miR-145, a tumor suppressor with many tumor-specific targets that regulates tumor growth, invasion and metastasis. CDK1 and SOX9 expression increases in multiple cell lines that are resistant to the chemo drug cisplatin; when both proteins are silenced, the cells become sensitive to chemotherapy. 

Al-Mathkour said she wants to find ways to “improve the treatment for patients with resistance to chemotherapy.” One approach is to understand chemoresistance at a mechanistic level.