Published online 23 March 2011 | Nature | doi:10.1038/news.2011.178

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Mutations block lung-cancer treatment

Revealing the genetic changes that let tumours escape drugs offers hope for combination therapies.

Heidi Ledford

Lung cancers can resist drugs from the outset, or develop resistance over time.Du Cane Medical Imaging/Science Photo Library

Tumours have many ways to dodge drug therapies, even those that are genetically targeted to attack them, two studies published today reveal. By uncovering these escape routes, researchers hope that therapies can be tailored to cut them off.

Both studies focus on lung cancers with genetic mutations that activate a protein called epidermal growth factor receptor (EGFR). Improper activation of this protein can lead to uncontrolled cell division, a hallmark of cancer. Two drugs — gefitinib (Iressa) and erlotinib (Tarceva) — block EGFR in tumours with activating mutations to prevent tumour growth.

These drugs help most patients: about three quarters of those with EGFR-activating mutations respond well to gefitinib, for example. But the rest respond poorly, if at all, and no one knows why.

"There is tremendous variation in response in patients with what look to be the same lesions," says Charles Sawyers, a cancer researcher at the Memorial Sloan-Kettering Cancer Center in New York and lead author of one of the studies.

Resisting arrest

One cause of this variation, Sawyers reasoned, could be that other genes modify a patient's response to the drugs. To test this, he and his colleagues ran experiments on a line of cultured cancer cells with EGFR-activating mutations that respond poorly to EGFR inhibitors.

The researchers used RNA interference to reduce the activity of cancer-related genes, and then tested the cells to determine whether this made them more sensitive to drug treatment. The findings are published in Nature¹.

Of more than 2,000 genes screened by the team, 36 affected sensitivity to EGFR inhibitors. Half of those are linked to cellular signalling pathways involving a single protein called NF-κB, which governs many stress responses, and has been targeted by some pharmaceutical companies looking to develop anti-inflammatory drugs.

Sawyers's results suggest that NF-κB inhibitors, used in combination with EGFR blockers, could fight recalcitrant tumours. The team found clinical evidence to back this up: in a trial of 52 people with lung cancer, those with high levels of a protein that inhibits NF-κB responded better to erlotinib than those with low levels.

The team is now testing the combination therapy in animal models.

The results are exciting and could lead to new cancer therapies, says William Pao, a cancer researcher at Vanderbilt University in Nashville, Tennessee.

The method could also be used to find genes that modify drug responses in other tumours, he says. For example, drugs called B-RAF inhibitors have shown promise in patients with advanced melanoma who carry a mutation that activates the protein B-RAF. But once again, the drug fails about 20% of these patients. Combination therapy could help that 20%.

Workarounds

Cancer therapies have another problem: even if a patient responds well at first, the drugs eventually fail. "The tumour melts away, and then it comes back," says Daniel Haber, director of the Massachusetts General Hospital Cancer Center in Charlestown.

The effects of EGFR inhibitors typically last a year before the tumours, now drug-resistant, return. Combination therapies could also help in this case, but it is first necessary to characterize the many ways that a tumour can shield itself from the drugs.

In the second study, Jeffrey Engelman, a cancer researcher at the Massachusetts General Hospital, and his team characterized resistant tumours in 37 patients.

Many had additional EGFR-related mutations, which allowed the protein to dodge inhibitors. Others had extra copies of the METgene, which spurs cancer growth. Both of these mutations had already been identified in drug-resistant tumours.

But some tumours behaved unexpectedly, by amplifying the gene for EGFR or picking up mutations in another cancer-promoting gene, called PIK3CA. The results are published in Science Translational Medicine².

Five tumours had transformed from non-small-cell lung cancer to small-cell lung cancer, which is responsive to different kinds of chemotherapy. And in three patients, repeated biopsies showed that, over time, drug-resistant cells had once again become vulnerable to the inhibitors.

On target

The results highlight the importance of monitoring tumours throughout treatment, says Paul Workman, a molecular pharmacologist at the Institute of Cancer Research in Sutton, UK. Traditionally, cancer treatment is based on the results of a single biopsy during initial diagnosis. Sampling tumours is invasive, and repeated biopsies can be difficult to justify — particularly in lung cancer, when each biopsy carries a small risk of lung collapse, says Haber.

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But Engelman points out that serial biopsies paid off for some patients. Those who developed small-cell lung cancer could receive chemotherapy that would not have been tried in a non-small-cell lung cancer. Some of those patients, he notes, had "remarkable" responses to the treatment.

Nevertheless, finding so many paths to drug resistance means that patients will need an arsenal of possible drug combinations to conquer the disease. "It is humbling to see the many resistance mechanisms that can occur," says Engelman. "It underscores the challenges ahead." 

• References

  1. Bivona, T. G. et al. Nature 471, 523-526 (2011). | Article |
  2. Sequist, L. V. et al. Sci. Trans. Med. 3, 75ra26 (2011).