EGFR Inhibitors May Induce Tumor Stemness

Published OnlineFirst May 22, 2014; DOI: 10.1158/2159-8290.CD-NB2014-073

NEWS IN BRIEF

on the cells in vitro and in vivo, the Ceritinib Gains FDA researchers found. They implanted immune-defi cient mice with tumor Approval for Lung Cancer cells that either carried or lacked Novartis’s second-generation ALK β the 3 integrin subunit. Only cells inhibitor ceritinib (Zykadia) has been that harbored the subunit sustained granted accelerated approval by the FDA, tumor growth and remained resistant offering a much-needed treatment option to erlotinib and lapatinib. for patients with certain lung cancers Clinical data supported these who relapse after fi rst-line therapy. results. Biopsies from lung cancer Approval was based on a pivotal patients whose disease had pro- phase I trial of 163 patients with A fully humanized monoclonal antibody, gressed on erlotinib showed higher metastatic ALK-positive non–small cell ramucirumab binds to VEGFR-2 (above), a main levels of CD61 than did biopsies lung cancer (NSCLC) who progressed driver of angiogenesis in tumors. It blocks from patients who hadn’t received on treatment with the ALK inhibitor the VEGFR-2 ligands VEGF-A, VEGF-C, and the drug, Cheresh and colleagues crizotinib (Xalkori; Pfi zer) and were VEGF-D. described in the study. given ceritinib. The overall response Drugs such as EGFR inhibitors rate was 54.6% with a median duration Taking data from both trials into can induce metabolic stress in a of response of 7.4 months. Side effects account, Fuchs believes “this really sets tumor, prompting some tumor cells included diarrhea, vomiting, dehydra- the mark, namely that ramucirumab- to adapt so they can survive. One tion, elevated liver enzymes, and low based regimens should be the stand- of their responses is to upregulate phosphorous levels. ard of care for second-line therapy.” CD61. “Tumor cells that exploit this “We now know that when crizo- He now wants to see ramucirumab mechanism become very stem-like,” tinib stops working, we have the tested against standard fi rst-line says Cheresh. “Moreover, these CD61- option of treating those patients chemotherapy for stomach cancer, but expressing cells are particularly dan- with a more potent ALK inhibitor,” acknowledges that determining this gerous, as they tend to metastasize to says Alice Shaw, MD, PhD, a thoracic standard may be challenging, as there a greater degree” than do cells lacking oncologist at Massachusetts General is “not necessarily a clear winner” the marker, he says. Hospital Cancer Center in Boston among currently available treatments. By tracing the molecular chain and the phase I trial’s lead investiga- “I don’t know that drugs targeting of events inside the stem-like cells, tor. “Ceritinib appears to be effective VEGF receptors are superior to those the researchers uncovered a way to against many of the known resistance that go after VEGF ligands,” adds switch them back. They found that mutations that arise in patients who Fuchs, “but I don’t think there’s any CD61 interacts with KRAS and RalB have been exposed to crizotinib.” question that VEGF inhibition has at the plasma membrane, resulting Compelling preliminary results activity in gastric cancer.” ■ in increased activation of TBK1 and led the FDA to designate ceritinib as NF-κB. Cells require this pathway to a Breakthrough Therapy in March EGFR Inhibitors May take on stem-cell characteristics and 2013 and grant accelerated approval become drug resistant. based solely on phase I data, which is Induce Tumor Stemness Drugs that disrupt the NF-κB unusual, says Shaw. EGFR inhibitors such as erlotinib pathway are available, including “Three years from the beginning of (Tarceva; Genentech/Astellas) and bortezomib (Velcade, Millennium), drug development to approval is very lapatinib (Tykerb; GlaxoSmithKline) a treatment for multiple myeloma fast,” she says. “It signals that the FDA generate drug-resistant cells that that hasn’t proven effective for solid is trying to move these drugs along to resemble cancer stem cells, research- tumors. However, Cheresh and col- give access to patients who may have ers report in a new study (Nat Cell leagues showed that the combination no other treatment options.” Biol 2014;16:457–68). They also of erlotinib and bortezomib curtailed Investigators noted that tumor uncovered the mechanism behind lung tumor growth in mice and regression was seen in patients with and this conversion and propose a treat- eliminated the CD61-expressing cells without ALK alterations, suggesting ment approach that may counteract it from the tumors. “We could revert the that ceritinib may be effective in patients and restore tumor cells’ susceptibility. cells to a more drug-sensitive state,” resistant to crizotinib even in the absence A team led by David Cheresh, PhD, he says. of a secondary ALK resistance mutation. and Laetitia Seguin, PhD, of the Later this year, a team led by Hatim Many patients with ALK-rearranged University of California, San Diego, Husain, MD, at the Moores Cancer tumors, which account for about 5% of Moores Cancer Center in La Jolla, Center will test Cheresh and Seguin’s all cases of NSCLC, respond well to discovered that, with erlotinib model of tumor drug resistance in the initial treatment with crizotinib but tend treatment, tumor cells expressed clinic. Patients who develop resistance to relapse within the fi rst year of treat- the marker CD61, also known to erlotinib will be given the combina- ment due to acquired resistance. Based α β as integrin v 3. The presence of tion of bortezomib and erlotinib with on results from this trial, a more potent CD61 was enough to confer stem- the hope that the tumors will respond ALK inhibitor, such as ceritinib, may cell attributes and drug resistance just as they did in mice. ■ overcome that resistance, says Shaw.

JULY 2014CANCER DISCOVERY | 753

EGFR Inhibitors May Induce Tumor Stemness

Cancer Discovery 2014;4:753. Published OnlineFirst May 22, 2014.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2014-073

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