Oncogene Addiction and the Rationale for Molecular Targeted Therapy in Lung Cancer

A Conversation With Fadlo R. Khuri, MD


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Over the past decade, Fadlo R. Khuri, MD, Professor and Roberto C. Goizueta Distinguished Chair of Hematology and Medical Oncology, and Deputy Director of the Winship Cancer Institute of Emory University, Atlanta, has focused his research and clinical career on investigating novel approaches in the treatment and prevention of lung and upper aerodigestive tract cancer. His studies—for example, showing that the expression of retinoic acid receptor (RAR) and cyclooxygenase (COX)-2 indicate poor prognosis in lung cancer and prognostic factors such as death-associated protein kinase (DAPK) methylation and lack of interleukin (IL)-10 expression independently predict cancer-specific survival—have spurred a greater understanding of individualized adjuvant therapy for patients with lung cancer.

Dr. Khuri’s research in the development of novel cancer drugs has also led to new opportunities to target drivers of oncogene addiction, a phenomenon that describes the use of therapies to enhance the dependency of cancer cells to certain signaling pathways, such as EGFR, ALK, ROS, and RET.

Earlier this year, Dr. Khuri was recognized for his research accomplishments in lung and aerodigestive medical oncology at the American Association for Cancer Research Annual Meeting, where he received the Richard and Hinda Rosenthal Memorial Award.

In July, Dr. Khuri gave a review of new developments in novel therapeutics for lung cancer at the Debates and Didactics in Hematology and Oncology conference held on Sea Island, Georgia. The ASCO Post talked with him about his presentation, the phenomenon of oncogene addiction, progress being made in lung cancer survival, and the danger of the growing popularity of electronic cigarettes.

Oncogene Addiction

Please explain the phenomenon called oncogene addiction and how it provides a rationale for molecular targeted therapy.

My original medical school mentor, Dr. I. Bernard Weinstein, coined the term “oncogene addiction” in 2002. It indicates that cancer cells, which develop a dependency on certain oncogenically driven pathways, become disproportionally dependent on those pathways. Examples include EGFR and ALK in lung cancer and HER2/neu in breast cancer. The classic example is BCR-ABL in chronic myelogenous leukemia. Interrupting those pathways by targeting the kinase domain mutation or blocking the oncogenic signaling in some manner makes the cancer cells much more vulnerable than normal cells because the normal cells are not as “addicted” or dependent on those pathways.

Targeting drivers of oncogene addiction has been an area of explosive progress in the past decade. In our view, however, most lung cancer cells are not simply addicted to one oncogenic driver mutation. At the Lung Cancer Mutation Consortium, we looked at over 1,000 lung cancer cases and identified oncogenic drivers in about 64% of those patients. Some of the driver mutations such as EGFR, ALK, ROS, or RET are targetable with novel agents. For others, like RAS, we don’t yet have great drugs or approaches for targeting them.

Ultimately we should be able to target the majority of lung adenocarcinomas or squamous cell lung cancers. The challenge will be in overcoming drug resistance that emerges in tumors with those mutations. Drug resistance often develops when the tumor cell acquires a second mutation, which has been shown in some of the ALK and VEGFR data. But we are looking at survival signaling networks to see if there is a way to interrupt or reroute the whole network, using the cancer cell’s dependence on the pathway to make it even more addicted, so that a second hit along that signaling network with a targeted therapy will be devastating for the cancer, without causing serious side effects.

Resistance Mechanisms

Which resistance pathways have emerged in lung cancers for first-generation targeted therapies?

Some agents such as crizotinib (Xalkori) are effective at targeting MET amplification and ALK and are already in use in the clinic. We are developing agents that target the second EGFR T790 mutation. So it’s an exciting time because we have developed not only drugs that can target reasonably effective approaches to the initial oncogenic driver mutation but also approaches to the second escape mechanism. There is a lot of work going on now in resistance mechanisms and the development of therapies to target them. These are advances patients didn’t have 5 or 10 years ago.

KRAS Mutations

In your presentation, you said that targeting KRAS-mutant lung cancer is still a challenge. Could you expand on that?

One of the major points of my presentation was about the heat shock protein (Hsp)90 inhibitors and the ­GALAXY-1 trial, which combined the Hsp90 inhibitor ganetespib with docetaxel vs docetaxel alone for second-line therapy of lung adenocarcinoma. Although the study data were promising, overall it was a cautionary tale.

I was one of the coauthors on the GALAXY-1 abstract presented at the ASCO Annual Meeting this year,2 and we had very interesting data suggesting that ganetespib plus docetaxel vs docetaxel alone seemed to show an advantage in progression-free survival. But that benefit was not specific to patients with KRAS mutations, which is where some of our original hope was, because this is a mutation for which we don’t yet have effective therapies. So here was a trial that looked positive, particularly in patients who didn’t have early progression, but people were still disappointed that it didn’t seem to specifically target KRAS-mutant lung cancers.

Immunotherapy

How effective are immunotherapies such as PD-L1 in the treatment of lung cancer?

Early data on immunotherapy in lung cancer show that responses are small but meaningful. What is interesting about these responses is that they are durable.

Now that we have more evidence from clinical studies, we’re starting to understand who can have a really durable response, based on patient biomarkers. But I don’t think we have the final answer on PD-L1 because PD-L1 staining on the tumors of about 20% of responders has been negative.

Longer Remissions, No Cures

More effective therapies have resulted in extended remissions for patients with advanced lung cancer. Is it now possible to cure some patients with advanced disease?

So far, we have been successful in achieving longer remissions but not cures. When I started my residency, patients with lung cancer were living 3 to 4 months and chemotherapy was experimental. Now, patients with metastatic disease live 1 year longer on average.

We’re not very good yet at detecting disease early, but we are getting better. Some of the barriers to early detection include insufficient application of smoking cessation programs and of routine screening. Just as in diseases like diabetes, you want to get good control early on in lung cancer.

E-Cigarettes

A recent story in The New York Times reported on the popularity of electronic cigarettes,2 which use a nicotine solution instead of tobacco and emit a smoke-like water vapor. What is your take on e-cigarettes?

I’m not in favor of e-cigarette use. We need to have more complete approaches to smoking cessation programs. I’ve seen these failures, and they don’t help people stop smoking. It is also very troubling that young people are adopting the practice of e-cigarettes because, while they may seem cool and harmless, e-cigarettes could well put people on the path to picking up a cigarette again.

We know that smoking tobacco impacts on cancer survival and on second primary tumor development. It causes erratic metabolism of chemotherapy as well as increasing perioperative risk in potentially curable patients. To help patients quit smoking, oncologists need to be not just documenting smoking status, but implementing smoking cessation approaches for their patients. ■

Disclosure: Dr. Khuri reported no potential conflicts of interest.

References

1. Ramalingam SS, Goss GD, Andric ZG, et al: A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). 2013 ASCO Annual Meeting. Abstract CRA8007. Presented June 3, 2013.

2. Kurutz S: Smoking is back, without the stigma. New York Times. August 7, 2013.


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