Lung cancer is the second-most common cancer and the leading cause of cancer death in the United States.<\/p>\n
Over 80% of lung cancers are non-small cell lung cancers, in which tumor cells are larger and grow more slowly than those in small cell lung cancer.<\/p>\n
Many gene mutations are associated with non-small cell lung cancer, including the gene\u00a0KRAS, which is important for cell growth and division and is mutated in 30% of cases.<\/p>\n
Patients with tumors that have these mutations have shorter survival times and often become resistant to therapies.<\/p>\n
In a study published in\u00a0The Journal of Clinical Investigation,\u00a0University of Michigan researchers found a new protein target and developed a drug to treat non-small cell lung cancers that have\u00a0KRAS\u00a0mutations.<\/p>\n
“There are several FDA-approved drugs that target KRAS in pancreatic, colon and lung cancer,” said Goutham Narla, Louis Newburgh Research Professor of Internal Medicine and member of Rogel Cancer Center.<\/p>\n
“Although they work well, tumor cells gain resistance after a short period of time.”<\/p>\n
The current study focused on protein phosphatase 2A, which has been shown to inhibit lung cancer development<\/a>.<\/p>\n PP2A is made up of three proteins that must bind to each other for the protein to function properly.<\/p>\n
<\/p>\n There are several FDA-approved drugs that target KRAS in pancreatic, colon and lung cancer. Although they work well, tumor cells gain resistance after a short period of time.”\u00a0<\/p>\n
Goutham Narla, M.D., Ph.D.<\/p>\n
<\/p>\n The inability of PP2A to assemble is commonly seen in lung, prostate and liver cancer, which led the researchers to ask whether stabilizing the complex can help inhibit tumor growth.<\/p>\n Using cell lines of non-small cell lung cancers with\u00a0KRAS\u00a0mutations, the team showed that anti-cancer drugs adagrasib and trametinib destabilized PP2A.<\/p>\n This finding could explain why patients eventually become resistant to these therapies. However, when a molecular glue called RPT04402 was added, the PP2A complex stabilized and led to cancer cell death.<\/p>\n The researchers confirmed these findings in mouse models and found that the molecular glue caused tumors to shrink.<\/p>\n The combination of adagrasib or trametinib with RPT04402 delayed resistance and increased the treatment effectiveness to over 150 days in mice.<\/p>\n “Although we tested several cell lines and animal models, we don’t know whether this combination will work in every case of non-small cell lung cancer,” Narla said.<\/p>\n “Our findings represent 20-30% of all small cell lung cancer cases.”<\/p>\n The team plans to start clinical trials in the near future in collaboration with Spring Works Therapeutics and Merck.<\/p>\n They also hope to extend this study to include other KRAS-mutant tumors and evaluate whether the drug combination works in pancreatic and colon cancers.<\/p>\n Source:<\/p>\n Michigan Medicine – University of Michigan<\/a><\/p>\n Journal reference:<\/p>\n
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