microRNA Expression Controls Lung Cancer Drug Resistance

microRNA Expression Controls Lung Cancer Drug Resistance

In the United States, lung cancer is the second most common cancer and the leading cause of cancer-related deaths. 1 in 4 cancer-related deaths are from lung cancer. While there are effective treatments for many cancers, lung cancer can be difficult to treat.

One of the main reasons why lung cancer treatment may not be effective, is cancer cells develop resistance to chemotherapeutic drugs during treatment. Once resistance develops, the prognosis is poor.

Researchers have been studying the mechanisms involved in drug resistance in lung cancer, with one recent study indicating drug resistance occurs due to microRNA miR-335 expression.

Around 15% of non-small cell lung cancers have a mutation on growth receptor EGFR which causes the cancer cells to grow at an uncontrollable rate. Drugs have been developed that can inhibit EGFR and kill cancer cells, but oftentimes the tumors return.

The latest study showed that a small number of cancer cells do not rely on EGFR for survival, instead they rely on a gene called AXL and are therefore resistant to drugs targeting EGFR. The study showed that cancer cells can also switch between drug sensitive and drug resistant states through microRNA miR-335 expression.

After receiving chemotherapy to kill the cancer cells, random modifications constantly occur in the cells that remain. While the cells that rely on the AXL gene grow back, so do cells that rely on EGFR for survival. “Augmented levels of AXL and GAS6 have been found to drive resistance to EGFR tyrosine kinase inhibitors such as Erlotinib and Osimertinib in certain tumors with mesenchymal-like features,” explained researcher Raffaella Sordella, PhD.

The researchers studied how AXL-positive cells developed and found a previously unknown mechanism of drug resistance involving cell state transition, with the mechanism involved in switching cells between the two states centered on the epigenetic regulation of miR-335.

miR335 was found to determine the state of cancer cells. If a cancer cell loses miR335, events are triggered that allow the cell to use the alternative AXL pathway, which means the tumor will grow back and will be resistant to treatment.

Now that this mechanism is better understood, drugs need to be developed that can be used to target the AXL-dependent cells. Used in combination with current drugs, it could allow cancer cells to eradicated permanently.

You can read more about the study in the paper – An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression – which was recently published in eLife. DOI: 10.7554/eLife.66109