Thwarting Drug Resistance in Lung Cancer

If you’ve read up on lung cancer research in the last few years, you probably know that large strides have been made in targeted therapies for non-small cell lung cancer (NSCLC). Targeted therapies are drugs that identify and attack specific mutated proteins that are detected in tumors. Because noncancerous cells do not have these specific mutations, targeted therapies can make a beeline for cancer, while leaving healthy tissue unharmed.

But targeted therapies are by no means a perfect solution. During treatment with a targeted therapy, a patient’s tumors can develop new mutations that make them resistant to the drug. Oncologists are working out how to treat patients who have developed resistance to targeted therapies—and how to prevent resistance in the first place.

A substantial percentage of NSCLC tumors harbor mutations in genes (DNA) that encode proteins called receptor tyrosine kinases (RTKs). Recurrent mutations make RTKs abnormally active, unleashing a cascade of cellular signaling events that culminate in runaway cancer cell multiplication and tumor growth. Four RTKs—EGFR, ALK, ROS, and RET—are targets of drugs that inhibit their function and slow down or even stop tumor growth. The U.S Food and Drug Administration (FDA) has approved drugs that target mutant EGFR (erlotinib [Tarceva], gefitinib [Iressa], and afatinib [Gilotrif]) and mutant ALK (crizotinib [Xalkori] and ceritinib [Zykadia], which was approved just last week).

Unfortunately, the beneficial effects of so-called ‘RTK inhibitor’ drugs are often short-lived, as patients’ tumors become resistant over time. By now, scientists have worked out some of the cellular mechanisms that underlie this resistance in NSCLC.

The best-known path to RTK inhibitor resistance is when the already-mutated RTK gene itself develops secondary mutations that make the resulting protein impervious to RTK inhibitors. For example, a specific EGFR mutation called T790M is found in the tumors of 60% of patients who become resistant to the EGFR-targeted drug Tarceva. For these patients, scientists have developed ‘second-generation’ inhibitors that can overcome resistance rooted in new mutations. Several clinical trials are testing new targeted drugs, including CO-1686, AP26113, and AZD9291, to see whether they are effective for patients with the T790M-resistance mutation.  All three drugs have shown very promising activity in preliminary reports from the trials.  Zykadia, just approved by the FDA for cancers with mutations in the ALK gene, is actually a second-generation inhibitor that shuts down the activity of the ALK protein, even after it acquires a mutation that makes it resistant to the earlier-approved drug Xalkori.

An alternative approach is to combine RTK inhibitors with other drugs in an attempt to forestall resistance. This is a difficult but potentially rewarding endeavor. The difficulty lies in choosing the right combination of drugs. For example, a second drug in the drug combo could target another protein that is abnormally activated by the mutant RTK targeted by the first drug in the combination. Mutant EGFR is known to activate other proteins called AKT, MEL, and mTOR (among others). The abnormal activity of these proteins induced by mutant EGFR contributes to the growth and metastasis of cancer, even though the proteins themselves are usually not mutated. Ongoing clinical trials are testing treatments that combine Tarceva with drugs inhibiting these proteins. Other mechanisms of resistance to EGFR inhibitors involve the activation of additional RTKs, in particular MET and HER2. Again, ongoing trials are testing treatments that target these proteins in addition to EGFR. The hope is real, but, as I described in an earlier post, so are the difficulties.

Much research is being conducted to uncover additional mechanisms of resistance to targeted inhibition of RTKs in NSCLC, and new discoveries are made with some regularity. Just last week, a study published in the scientific journal Cancer Discovery identified low levels of the protein NF1 in lung tumors as another culprit in causing resistance to Tarceva. Interestingly, deleterious mutations in or the loss of NF1 are known to be involved in the resistance of melanoma tumors to the targeted drug Zelboraf. Fortunately, there are drugs in clinical trials that could correct the damaging consequences of low NF1 activity in lung cancer.

Meanwhile, scientists are making progress in developing immunotherapy treatments for lung cancer. Immunotherapies boost a patient’s own immune system to fight cancer. New clinical trials testing promising drugs called immune checkpoint antibodies seem to proliferate, which is great news. Just a few days ago, the initiation of a new phase III trial testing an immunotherapy drug called MEDI4736 was announced. For the uninitiated, immunotherapies do not rely on specific mutations in tumors, but much work will have to be done to understand why they work in many, but not all patients.