2021 LCRF-AstraZeneca Research Grant
Lior Golomb, PhD
Dana-Farber Cancer Institute
Research Project:
Investigating the ER Acetyl-CoA transporter as a putative metabolic dependency of mutant EGFR lung cancer
Summary:
A large percentage of all newly diagnosed lung tumors have specific mutations in the epidermal growth factor receptor (EGFR) gene. These patients are often treated with a class of drugs that unlike traditional chemotherapy, target the mutated gene with high precision, killing only the cancer cells. Osimertinib is the leading drug used to treat patients with advanced lung cancer that harbor EGFR specific mutations. Osimertinib shows remarkable specificity, potency and reduced toxicity compared to drugs of the same class but unfortunately, all patients treated with osimertinib or other EGFR-targeting drugs, eventually relapse. To understand the mechanisms that drive osimertinib resistance, Dr. Golomb has been conducting a comprehensive study using cutting-edge genetic engineering technology to study how resistance to osimertinib develops and how to make these tumors more susceptible to existing therapies. Through that effort he discovered that EGFR positive lung cancer cells are sensitive to targeting of a key metabolic gene called SLC33A1. The LCRF-AstraZeneca grant will enable him to study this discovery in depth and will hopefully lead to the development of new drugs and therapeutic schemes to delay osimertinib resistance and significantly extend the lives of lung cancer patients.
Final report:
SLC33A1 is a protein coding gene that encodes a transmembrane transporter for acetyl-CoA and O-aceylated gangliosides. It acts as an important metabolic regulator that maintains acetyl-CoA homeostasis by promoting functional crosstalk between different intracellular organelles. The researcher shows that SLC33A1 knockout can increase sensitivity to both covalent and non-covalent EGFR TKIs. SLC33A1 knockout results in decreased EGFR phosphorylation and a decrease in ERRFI phosphorylation (also known as MIG6), an EGFR regulatory protein. Aim 2 planned to investigate SLC33A1 as a metabolic dependency of osimertinib resistant cells. The preliminary results suggest that NRF2 plays a role in driving resistance to EGFR TKIs and that cells in which NRF2 is activated are particularly sensitive to SLC33A1 knockout. It was found that SLC33A1 knockout results in a significant metabolic shift that is consistent with increased NRF2 activity, including an increase in glutathione levels and other redox related metabolites. A decrease in Acetyl-CoA levels following SLC33A1 knockout was observed. Cyclosporine A (CsA) with osimertinib decreases the IC50 of osimertinib in EGFR mutant NSCLC cell lines. The same effect was also achieved using 3 other CsA derivatives: voclosporin and the two non-immunosuppressive cyclophilin inhibitors, NIM811 and alisporivir. The combination treatment showed significant effect both at day 24 and at the experiment end point, suggesting combination of CsA or NIM811 with osimertinib can significantly increase response to osimertinib and reduce residual disease. There was a strong correlation between the response of cells to CsA treatment and SLC33A1 knockout, including sensitization of EGFR mutant cells to osimertinib and synthetic lethality with glutathione biosynthesis.
Impact:
The work that has been done is at a very basic level. The premise is that a metabolic abnormality can be identified that can be targeted to improve response and/or overcome resistance to osimertinib in EGFRmut+ NSCLC. Even though the results are very early the researcher has identified cyclosporin A and other similar drugs may act in conjunction with osimertinib to improve responses in persister cells and potentially overcome resistance. Because these drugs are available there is potential translation of these findings to a clinical trial. Of course, more work will need to be done before this is realized.