Image of two lung cancer cells. Image credit: Anne Weston, Francis Crick Institute (CC BY NC)
Organisms keep their tissues healthy by instructing damaged or unwanted cells to kill themselves via a controlled process known as apoptosis. Cancer cells, however, are able to evade death by increasing the level of proteins that block apoptosis, such as MCL1.
Researchers have recently developed new drugs that can inhibit the action of the MCL1 protein. But a number of cancers have become resistant to these inhibitors. So, one important question is whether other proteins in cancer cells could be drugged, together with MCL1, to overcome or even avoid this resistance.
Now, Kabir et al. have addressed this question by searching the genome of human lung cancer cells, which were resistant to treatment, for targets that could improve the performance of two MCL1 inhibitors. This involved reducing the level of every protein in these cells one by one using a genetic technique known as CRISPR-Cas9, and looking for cells that lost their resistance to the MCL1 inhibitor.
From these genetic screens, Kabir et al. identified three proteins that are part of complex called CRL5. Inactivating this protein complex caused cancer cells to become more sensitive to the MCL1 inhibitor. Further biochemical experiments showed that CRL5 may contribute to drug resistance by reducing the levels of two proteins that promote apoptosis.
These findings suggest that inhibiting CRL5 in combination with MCL1 could combat drug resistance. Although there are currently no drugs against CRL5, future experiments determining how CRL5 and MCL1 are linked could identify new drug targets and improve existing cancer treatments.
