Erbb Signaling Interrupted: Targeting Ligand-Induced Pathway Activation Frederick H

Home , ErbB, ERBB3, ErbB4, Tyrosine kinase

VIEWS

IN THE SPOTLIGHT eRBB signaling Interrupted: Targeting Ligand-Induced Pathway Activation Frederick H. Wilson 1 ,2 ,3 and Katerina Politi 1 ,3 ,4 summary: A patient with advanced lung adenocarcinoma harboring a CD74–NRG1 gene rearrangement, which promotes ERBB2–ERBB3 heterodimerization and activation of downstream signaling, had an exceptional therapeutic response to an experimental anti-ERBB3 antibody. This result illustrates how NRG1 rearrangements, which are observed at a low frequency in a variety of solid tumors, may represent tractable therapeutic targets. Cancer Discov; 8(6); 676–8. ©2018 AACR.

See related article by Drilon et al., p. 686 (7).

Members of the EGFR family of receptor tyrosine kinases this family of RTKs occur in tumors (3 ). Moreover, mutations (RTK) transduce cues from the extracellular environment into the in ligands that regulate the function of these receptors are also cell to regulate proliferation and survival in response to ligand- being discovered ( 4, 5 ). Initial studies of these rarer mutations induced homodimerization and/or heterodimerization. The four suggest that many are oncogenic and can be targeted using EGFR family members (EGFR/ERBB1, ERBB2/HER2, ERBB3, ERBB-directed therapies ( 6 ). However, our understanding of and ERBB4) are all single-chain transmembrane receptors with a the oncogenic properties of many of these mutations and tyrosine kinase domain but have distinct characteristics, ligands, the therapeutic vulnerabilities of the tumors harboring them and preferred dimerization partners ( 1 ). For example, ERBB3 has remains limited despite the availability of numerous agents weak kinase activity and relies on heterodimerization with other targeting components of the EGFR signaling network. RTKs for activation. In addition, EGFR, ERBB3, and ERBB4 In this issue, Drilon and colleagues report an exceptional each have several ligands, whereas ERBB2 has none. Interestingly, therapeutic response in a patient with advanced NRG1 -rear- there is partial overlap in ligand specifi city such that EGFR and ranged lung adenocarcinoma treated with an investigational ERBB4 share three ligands and the ERBB3 ligands NRG1 and anti-ERBB3 mAb (GSK2849330) as part of a phase I clini- NRG2 also bind ERBB4. The ligands induce receptor dimeriza- cal trial (Fig. 1 ; ref. 7 ). The patient had previously received tion and activation of downstream signaling. two lines of systemic chemotherapy and a third line of Several genetic alterations in the EGFR family are well- immunotherapy in the setting of disease recurrence follow- established cancer drivers ( 2 ). Most notable among these ing resection and radiation for early-stage disease. Prior to are ERBB2 overexpression in breast cancer and EGFR muta- trial enrollment, comprehensive molecular profi ling of the tions in lung adenocarcinoma. These common alterations are patient’s tumor revealed a somatic, in-frame gene rearrange- paradigms for precision oncology such that breast cancers and ment fusing exons 1–6 of CD74 with exons 6–13 of NRG1 to lung adenocarcinomas are routinely tested for ERBB2 overex- generate the chimera CD74–NRG1 , which retains the EGF- pression or EGFR mutations, respectively. Advanced tumors like domain responsible for receptor binding. This gene harboring these alterations are treated with molecularly tar- fusion was initially reported in 5 invasive mucinous lung geted agents such as ERBB2-directed antibodies and EGFR adenocarcinomas from never-smokers in 2014 (4 ). Ectopic tyrosine kinase inhibitors (TKI). However, through large-scale expression of CD74–NRG1 in cells leads to ERBB2–ERBB3 cancer sequencing efforts like The Cancer Genome Atlas heterodimerization and promotes cell survival and prolifera- (TCGA) and the increasingly widespread genomic profi ling of tion via activation of the MAPK and PI3K pathways (4 ). tumors, it is becoming clear that additional rarer mutations in The patient described in this report experienced a 90% reduction in tumor volume with a durable response to GSK2849330 lasting 19 months. The patient was subsequently treated with 1Department of Medicine, Section of Medical Oncology, Yale School of the EGFR family TKI afatinib but experienced further disease Medicine, New Haven, Connecticut. 2 Department of Genetics, Yale School progression after 8 weeks of therapy. Three additional targeted of Medicine, New Haven, Connecticut. 3 Yale Cancer Center, Yale School of therapy–naïve patients with NRG1 -rearranged lung adenocarci- Medicine, New Haven, Connecticut. 4 Department of Pathology, Yale School noma also did not respond to afatinib. In contrast, responses of Medicine, New Haven, Connecticut. to afatinib have been described in other isolated cases of NRG1 - Corresponding Authors: Katerina Politi, Yale School of Medicine, 333 rearranged lung carcinoma ( 5, 8 ). The authors note that no Cedar Street, SHM-I 234D, New Haven, CT 06510. Phone: 203-737-5921; Fax: 203-785-7531; E-mail: [email protected]; and Frederick H. Wil- other responses to GSK2849330 were observed among the 29 son, Yale Cancer Center, PO Box 208028, New Haven, CT 06520. Phone: clinical trial participants, who were enrolled on the basis of 203-737-5234; Fax: 203-785-4116; E-mail: [email protected] increased ERBB3 expression. This observation hints at a distinc- doi: 10.1158/2159-8290.CD-18-0368 tion between target expression and target activation in predict- © 2018 American Association for Cancer Research. ing response to ERBB3-directed therapies. Similarly, activating

676 | CANCER DISCOVERY june 2018 www.aacrjournals.org

CD74 Figure 1. Targeting ERBB activation mediated by CD74–NRG1. Schematic representation of the NRG1 potential consequences of either pan-ERBB TKIs Active heterodimer (such as afatinib, left) or an anti-ERBB3 antibody (such as GSK2849330, right) on ERBB2–ERBB3 Proliferation survival ERBB2 heterodimerization. In this model, the CD74–NRG1 ERBB3 fusion protein binds ERBB3, inducing heterodimerization with ERBB2 and stimulating cell survival Pan-ERBB TKI Anti-ERBB3 antibody and proliferation. A pan-ERBB TKI may partially inhibit ERBB2 kinase activity and modestly sup- press signaling, which, in some cases, may elicit antitumor effects in patients (5, 8). An anti-ERBB3 Y antibody may lead to more potent inhibition of Partially active heterodimer Impaired dimerization ERBB2–ERBB3 signaling, leading to tumor regres- and signaling and signaling sion (7). Proliferation Proliferation ERBB2 ERBB2

survival ERBB 3 survival X ERBB3

EGFR mutations (but not increased EGFR levels) are predictive The findings of this study suggest thatNRG1 rearrange- of response to EGFR-directed therapies in lung cancer. In ments may represent an actionable genetic alteration in lung contrast, ERBB2-directed antibodies have activity in breast, and other solid tumors. Given the low frequency of these esophageal, and gastric cancers with ERBB2 overexpression; this molecular alterations, innovative approaches to clinical trial suggests the relationships among expression, activation, and design will be essential to characterize the activity of emerging response to molecular therapies may be biologically complex. therapeutics in these rare patient populations. Although clini- Drilon and colleagues demonstrate that GSK2849330 inhib- cal trials have historically focused on homogeneous patient its phosphorylation of ERBB2, ERBB3, and AKT and impairs populations with a single tumor type, it may prove difficult to cell proliferation in MDA-MB-175-VII cells (a breast cancer cell identify sufficient patients withNRG1 -rearranged tumors of line harboring a DOC4–NRG1 fusion) and in HCC-95 cells (a a single tumor type to conduct prospective clinical trials. To lung cancer cell line with NRG1 amplification). Similar find- address similar challenges associated with the study of another ings were noted with the pan-ERBB inhibitors afatinib and rare genetic driver, a recent phase I–II study demonstrating neratinib. These cells were dependent on ERBB2 and ERBB3 activity of the selective TRK inhibitor larotrectinib in solid as evidenced by a reduction in growth with genetic depletion of tumors harboring TRK fusions incorporated 55 adults and either receptor. Although these cell-based studies revealed com- children with various TRK fusions encompassing 17 distinct parable antiproliferative effects of GSK2849330 and pan-ERBB tumor types (9). This follows on the heels of multiple studies inhibitors, only GSK2849330 induced tumor regression in an demonstrating activity of the anti–PD-1 antibody pembroli- ovarian cancer patient-derived xenograft (PDX) model with zumab across 15 microsatellite instability–high or mismatch a CLU–NRG1 fusion. Treatment with afatinib only impaired repair–deficient metastatic solid tumor types—findings that led tumor growth, consistent with partial inhibition of ERBB sign- to the first FDA approval of a cancer therapeutic in conjunc- aling (Fig. 1). Further studies will be required to reconcile these tion with a biomarker and agnostic to tissue of origin. These in vitro and in vivo findings with afatinib and to assess any clini- “basket” trials incorporating distinct tumor types harboring a cal role for this agent in the treatment of NRG1-rearranged solid common molecular alteration or biomarker have the potential tumors. Moreover, additional studies to investigate the specific to expedite clinical evaluation of promising genome-directed molecular mechanisms underlying the differences in sensitivity therapies. However, caution must be exercised in generalizing to afatinib and GSK2849330 in NRG1-driven tumors will be findings across tissue types due to tissue-specific differences in valuable. This would include examination of the dimerization response to targeted therapies in some contexts (10). patterns, activation, and total protein levels of all EGFR family Should formal clinical studies confirm activity of ERBB3- receptors (including EGFR and ERBB4) in the presence of dif- directed therapies in NRG1-rearranged lung tumors, NRG1 ferent NRG1 fusions exposed to the therapies. fusions would add to a growing number of targetable genetic Importantly, the authors note that among over 17,000 solid alterations in lung cancer. Currently, targeted therapies are tumors subjected to comprehensive DNA-based molecular approved for use in the treatment of advanced lung cancers profiling at their institution,NRG1 rearrangements were iden- harboring activating EGFR mutations, BRAFV600E mutations, tified in 0.14% of non–small cell lung cancers, 0.13% of pancre- and rearrangements involving ALK or ROS1. Additional emerg- atic adenocarcinomas, and 0.04% of breast cancers. Additional ing targets include activating HER2 mutations, MET exon 14 NRG1 rearrangements were identified from targeted RNA splice alterations, and rearrangements involving RET or NTRK. sequencing as well as whole-transcriptome sequencing of As the number of actionable genetic alterations in lung and tumors from the TCGA. Other smaller studies suggest that other cancers continues to rise, it will be essential to streamline NRG1 rearrangements in lung cancer may be enriched in never- molecular characterization of tumor specimens and circulat- smoker populations of Asian descent with invasive mucinous ing tumor DNA to achieve precision oncology patient care. adenocarcinoma (4). Although larger patient cohorts will be With only limited tissue from advanced solid tumors gener- necessary to explore these potential associations, the possibil- ally available for analysis, it will be impractical to assay for ity of a NRG1 fusion should be considered in the context of individual genetic alterations in a sequential manner. With the these pathologic and demographic features. growing recognition of diverse structural variants (including

june 2018 CANCER DISCOVERY | 677

Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2018 American Association for Cancer Research. Views targetable chimeric proteins with multiple potential fusion References partners), it may become increasingly important to incorpo- rate RNA-sequencing platforms into comprehensive tumor . 1 Lemmon MA, Schlessinger J, Ferguson KM. The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb Perspect genomic profiling to permit detection of fusion transcripts. Biol 2014;6:a020768. Members of the EGFR family of RTKs are critical thera- 2. Arteaga CL, Engelman JA. ERBB receptors: from oncogene discovery peutic targets in multiple tumor types. This study highlights to basic science to mechanism-based cancer therapeutics. Cancer Cell the potential for aberrant ligand expression to promote a 2014;25:282–303. dependency on ERBB3 signaling that could potentially be 3. Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, exploited for therapeutic purposes. Although the low fre- Weerasinghe A, et al. Comprehensive characterization of cancer driver quency of NRG1 rearrangements may pose challenges in the genes and mutations. Cell 2018;173:371–85. 4. Fernandez-Cuesta L, Plenker D, Osada H, Sun R, Menon R, Leenders clinical development of agents to overcome the effects of F, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov NRG1-mediated ERBB3 activation, it is essential to pursue 2014;4:415–22. promising therapies that may provide meaningful clinical 5. Cheema PK, Doherty M, Tsao MS. A case of invasive mucinous pul- benefit for individuals whose tumors harborNRG1 fusions. monary adenocarcinoma with a CD74-NRG1 fusion protein targeted with afatinib. J Thorac Oncol 2017;12:e200–e2. Disclosure of Potential Conflicts of Interest 6. Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell F.H. Wilson reports receiving a commercial research grant from Agios 2013;23:603–17. and is a consultant/advisory board member for Loxo Oncology. K. Politi 7. Drilon A, Somwar R, Mangatt BP, Edgren H, Desmeules P, Ruusul- reports receiving commercial research grants from AstraZeneca, Kolltan, ehto A, et al. Response to ERBB3-directed targeted therapy in NRG1- Roche, and Symphogen, is a consultant/advisory board member for rearranged cancers. Cancer Discov 2018;8:686–95. AstraZeneca, Merck, NCCN, Novartis, and Tocagen, and has received 8. Jones MR, Lim H, Shen Y, Pleasance E, Ch’ng C, Reisle C, et al. Suc- IP royalties from MSKCC/Molecular MD. cessful targeting of the NRG1 pathway indicates novel treatment strategy for metastatic cancer. Ann Oncol 2017;28:3092–7. Acknowledgments 9. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri This work was supported by Mentored Clinical Scientist Research GD, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in Career Development Award K08CA204732 (to F.H. Wilson) and Yale adults and children. N Engl J Med 2018;378:731–9. SPORE in Lung Cancer P50 CA196530 (to K. Politi). 10. Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3- Published online June 1, 2018. mutant cancers. Nature 2018;554:189–94.

678 | CANCER DISCOVERY june 2018 www.aacrjournals.org

Frederick H. Wilson and Katerina Politi

Cancer Discov 2018;8:676-678.

Updated version Access the most recent version of this article at: http://cancerdiscovery.aacrjournals.org/content/8/6/676

Cited articles This article cites 10 articles, 3 of which you can access for free at: http://cancerdiscovery.aacrjournals.org/content/8/6/676.full#ref-list-1

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerdiscovery.aacrjournals.org/content/8/6/676. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.