KRAS mutations are thought to cause a quarter of all cancer deaths by activating cell signaling pathways such as MAPK (mitogen-activated protein kinase) that drive cell proliferation and enhance cell survival.
"Several inhibitors of the MAPK pathway are FDA-approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell," Dr. Adam Renslo of the University of California, San Francisco (UCSF) and colleagues explain in the Journal of Experimental Medicine. Their study describes a novel therapeutic strategy that takes advantage of the KRAS-driven tumors' propensity to accumulate Fe.
"Oncogenic KRAS promotes an expanded pool of labile iron (labile iron pool, or LIP) in pancreas cancer cells and tumors," Dr. Renslo told Reuters Health by email. "MAPK signaling can be decoupled from LIP elevation in normal and tumor cells, and LIP elevation is targetable with a small molecule prodrug approach - iron-activated drug conjugates, or FeADC."
FeADCs are inactive versions of drugs that break apart in the presence of ferrous iron, releasing the drug's active version.
For the study, the researchers converted an FDA-approved MEK inhibitor, cobimetinib, into an FeADC. Laboratory tests showed that this drug conjugate, TRX-cobimetinib, had little effect on human skin or retinal cells but was activated inside KRAS mutant cancer cells, inhibiting the KRAS-MEK signaling pathway and blocking cell growth.
They then tested TRX-cobimetinib in different mouse models of KRAS-driven cancer, including pancreatic and lung adenocarcinomas. TRX-cobimetinib inhibited tumor growth as effectively as the approved drug, but caused no detectable damage to healthy tissues.
The team then combined TRX-cobimetinib with other anticancer drugs, including the SHP2 inhibitor, RMC-4550. Their laboratory analyses indicated the FeADC-based MEK inhibition combined with SHP2 blockade showed comparable efficacy and improved tolerability.
Dr. Renslo and a coauthor, Dr. Eric Collisson, are cofounders of Tatara Therapeutics, which has licensed the FeADC technology from UCSF and will be pursuing clinical translation of FeADCs in oncology.
Dr. Christopher Chang, professor of chemistry and of molecular and cell biology at the University of California, Berkeley, and senior editor, ACS Central Science, commented on the study in an email to Reuters Health. "This is an innovative study that highlights the growing connection between dietary nutrients and cancer. In this case, iron is an essential element for normal growth and development, as you get anemia without enough iron, but one can exploit the aberrant, elevated needs of tumors for even more iron than healthy tissue to create targeted drugs that have the potential to minimize side effects."
"Because of the modular nature of the approach and the fact that it exploits native metal-dependent cancer signaling pathways, it has value as a therapeutic platform," he said.
Dr. Chang led a consortium article outlining connections between cancer and copper (https://go.nature.com/3KT5RC9), noting that because copper also is an essential nutrient, "too much or too little copper can be leveraged for cancer detection and treatment."
"This is an exciting area to see come to the forefront of cancer metabolism," he concluded.
SOURCE: https://bit.ly/3tkFLC2 and https://bit.ly/3Ijsr5d Journal of Experimental Medicine, online March 9, 2022.
By Marilynn Larkin
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