EGFR Inhibitors May Induce Tumor Stemness

Published OnlineFirst May 22, 2014; DOI: 10.1158/2159-8290.CD-NB2014-074

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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

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“Ceritinib is anywhere from fi ve to signatures 2 and 13 and a deletion in NOTED 20 times more effective against ALK one APOBEC gene cluster that has than crizotinib, and it has a chemically been implicated in breast cancer. Seven • The FDA approved the cobas HPV DNA distinct structure,” she notes. It also APOBEC genes sit next to each other test for primary cervical cancer inhibits a different spectrum of targets; on chromosome 22, and the deletion screening in women ages 25 and older. for example, unlike crizotinib, ceritinib removes parts of the APOBEC3A and Manufactured by Roche Molecular does not inhibit the kinase activity of APOBEC3B genes. Next-generation Systems, the test can also provide MET but does inhibit the IGF-1 receptor. sequencing of more than 900 breast information about a patient’s risk for Investigators have now completed cancer tumors showed a relationship developing cervical cancer in the future. two phase II trials of ceritinib and are between the deletion and the number The agency first approved the test in awaiting results, says Shaw. One study of signature 2 and signature 13 muta- 2011 for use in conjunction with or as a focused on patients with acquired tions in the genome. follow-up to Pap testing. resistance to crizotinib, while the “People who have this deletion have • An in-depth analysis of data from one of other targeted crizotinib-naïve tumors. a greater likelihood of having breast the Women’s Health Initiative (WHI) In addition, two phase III randomized cancers that are heavily mutated with Postmenopausal Hormone Therapy studies are under way comparing this specifi c pattern,” says lead author Trials has found that the investment in ceritinib to standard chemotherapy, Serena Nik-Zainal, MD, PhD, also of the WHI by the NIH resulted in a return either combination chemotherapy or the Wellcome Trust Sanger Institute. of $140 for each dollar spent on the single-agent chemotherapy. Multiple signature 2 and signa- trial. In addition, they found that guid- “We’re looking to see that the effi cacy, ture 13 mutations also showed up ance provided by the trial’s results led to response rate, and duration of responses in patients with acute lymphoblastic 76,000 fewer cases of cardiovascular hold up in phase II trials,” explains leukemia and bladder cancer who disease; 126,000 fewer cases of breast Shaw. “We also need to carefully look at carry the deletion, the researchers cancer; 145,000 more quality-adjusted side effects and other potential toxici- reported (Nat Genet 2014;46:487–91). life years; and savings of $35.2 billion on ties in follow-up studies.” ■ The team added further evidence direct medical expenses. that the deletion prompts the char- • According to a survey of more than 1,000 acteristic mutations. When APOBEC Gene Deletion Speeds women by the American Lung Association, proteins make sequential edits, they women are largely unaware of their risk Mutation Rate tend to occur on the same DNA of lung cancer. Despite being the leading A deletion that eliminates an antivi- strand. In breast cancer tumors with cause of cancer mortality among women, ral gene in the APOBEC family leads to the deletion, these same-strand muta- lung cancer was cited by just 1% of women an explosion of mutations throughout tions are unusually common. as their primary cancer concern. the genome, researchers report. Not everyone with the deletion devel- APOBEC proteins combat viruses by ops a hypermutator tumor, and not ev- • The FDA granted “Priority Review” des- editing their nucleic acids. For example, eryone with numerous signature 2 and ignation to Merck’s investigational anti– one family member, APOBEC3G, con- 13 mutations carries the deletion. The PD-1 antibody MK-3475 for the verts cytidines into uridines in HIV’s deletion is “probably one of multiple treatment of advanced melanoma. A genome. Although APOBEC proteins contributing factors” that increase the decision is anticipated by October 28. are generally benefi cial, researchers have number of mutations, says Nik-Zainal. • Researchers found that nearly 70% of wondered whether the proteins’ actions What these other factors are isn’t clear. women who undergo prophylactic con- might also prompt cancer-causing The tantalizing mystery is how the dele- tralateral mastectomy have no clinically mutations. They’ve homed in on two tion leads to so many mutations. It elimi- significant risk factors for developing distinctive mutation patterns, known nates the coding region for APOBEC3B, cancer in the unaffected breast (JAMA as signature 2 and signature 13, that so individuals with the deletion lack Surg 2014 May 21 [Epub ahead of print]). might result from APOBEC activity. this protein. However, they produce a About 80% of those women said they These alterations affect three-nucle- functional form of APOBEC3A that’s opted for surgery to prevent disease otide sequences in which the fi rst two under control of the 3′-UTR regulatory recurrence even though the procedure bases are T and C—the C is typically region for APOBEC3B, so “you might be has not been shown to do so. altered to either a T or a G. getting a more mutagenic APOBEC3A,” • NIH Director Francis Collins, MD, PhD, told A team led by Michael Stratton, MD, says Nik-Zainal. members of the U.S. Senate Appropriations PhD, of the Wellcome Trust Sanger Although it might favor cancer, this Committee that the country is losing its Institute in Hinxton, UK, found that APOBEC3A variant could be benefi cial position as the world’s leader in science and these changes are prevalent in certain in some circumstances, Nik-Zainal innovation due to flat federal research fund- breast tumors and other cancers; some notes. The deletion is very common ing, irregular budget processes, sequestra- so-called hypermutator tumors can in parts of the world—93% of people tion, and inflation. “What we desperately harbor up to 70,000 of the mutations. from Oceania carry it—so it might pro- need is a new bipartisan plan to secure a In their new study, Stratton and vide some survival advantage, possibly steady funding trajectory for biomedical colleagues looked for a link between by increasing disease resistance. ■ research and ensure long-term stability for NIH’s mission.” For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.

754 | CANCER DISCOVERYJULY 2014 www.aacrjournals.org

Ceritinib Gains FDA Approval for Lung Cancer

Cancer Discovery 2014;4:753-754. Published OnlineFirst May 22, 2014.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2014-074

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