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Characterization of in Vivo Resistance to Osimertinib and JNJ-61186372

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Characterization of in Vivo Resistance to Osimertinib and JNJ-61186372 Published OnlineFirst August 22, 2017; DOI: 10.1158/1535-7163.MCT-17-0413 Cancer Biology and Translational Studies Molecular Cancer Therapeutics Characterization of In Vivo Resistance to Osimertinib and JNJ-61186372, an EGFR/Met Bispecific Antibody, Reveals Unique and Consensus Mechanisms of Resistance Kristina B. Emdal1, Antje Dittmann1, Raven J. Reddy1, Rebecca S. Lescarbeau1, Sheri L. Moores2, Sylvie Laquerre2, and Forest M. White1 Abstract Approximately 10% of non–small cell lung cancer (NSCLC) targeting EGFR/Met antibody, JNJ-61186372. Tumor-specific patients in the United States and 40% of NSCLC patients in Asia increases in tyrosine-phosphorylated peptides from EGFR family have activating epidermal growth factor receptor (EGFR) muta- members, Shc1 and Gab1 or Src family kinase (SFK) substrates tions and are eligible to receive targeted anti-EGFR therapy. were observed, underscoring a differential ability of tumors to Despite an extension of life expectancy associated with this uniquely escape EGFR inhibition. Although most resistant tumors treatment, resistance to EGFR tyrosine kinase inhibitors and within each treatment group displayed a marked inhibition of anti-EGFR antibodies is almost inevitable. To identify additional EGFR as well as SFK signaling, the combination of EGFR inhibi- signaling routes that can be cotargeted to overcome resistance, we tion (osimertinib) and SFK inhibition (saracatinib or dasatinib) quantified tumor-specific molecular changes that govern resistant led to further decrease in cell growth in vitro. This result suggests cancer cell growth and survival. Mass spectrometry–based quan- that residual SFK signaling mediates therapeutic resistance and titative proteomics was used to profile in vivo signaling changes in that elimination of this signal through combination therapy may 41 therapy-resistant tumors from four xenograft NSCLC models. delay onset of resistance. Overall, analysis of individual resistant We identified unique and tumor-specific tyrosine phosphoryla- tumors captured unique in vivo signaling rewiring that would have tion rewiring in tumors resistant to treatment with the irreversible been masked by analysis of in vitro cell population averages. Mol third-generation EGFR-inhibitor, osimertinib, or the novel dual- Cancer Ther; 16(11); 2572–85. Ó2017 AACR. Introduction understanding of the molecular mechanisms underlying resistant cancer cell growth and survival is required to direct future ther- Non–small cell lung cancer (NSCLC) remains the leading cause apies for advanced stage NSCLC. of cancer-related mortality, and its prevalence continues to To date, knowledge of therapy resistance mechanisms has increase worldwide (1). Activating mutations in the kinase facilitated the development of three generations of EGFR TKIs. domain of the epidermal growth factor receptor (EGFR) occur First-generation EGFR TKIs such as erlotinib and gefitinib bind at a high frequency in NSCLC patients, and are especially frequent competitively and reversibly to the ATP-binding site of the EGFR in never-smokers. Despite initial survival benefit from therapy tyrosine kinase domain. Clinical trials confirmed superior with EGFR tyrosine kinase inhibitors (TKI), overall patient sur- response rates and improved progression-free survival in NSCLC vival remains suboptimal and recurrence rates are high (2). Most patients with activating EGFR mutations, also known as sensitiz- patients experience acquired resistance to EGFR-targeted therapy ing mutations, such as L858R and the in-frame exon 19 deletion in less than a year after starting treatment (3–5). Even in the (ex19del) (4, 5, 8). However, about 50%–60% of patients acquire context of improved EGFR TKIs, overcoming therapeutic resis- resistance to TKI therapy through restored EGFR signaling con- tance remains a significant clinical challenge (6, 7). A better ferred by the secondary T790M EGFR gatekeeper mutation (8–11). Consequently, second-generation irreversible EGFR TKIs, 1Department of Biological Engineering and David H. Koch Institute for Integra- such as afatinib, dacomitinib, and neratinib, were introduced as a tive Cancer Research, Massachusetts Institute of Technology, Cambridge, Mas- fi 2 strategy to overcome rst-generation EGFR TKI resistance. How- sachusetts. Oncology, Janssen Research and Development, LLC, Spring House, ever, despite promising activity against T790M, these TKIs dis- Pennsylvania. played limited clinical efficacy due to dose-limiting toxicity Note: Supplementary data for this article are available at Molecular Cancer caused by simultaneous inhibition of wild-type EGFR (12). Therapeutics Online (http://mct.aacrjournals.org/). Ultimately, third-generation EGFR-TKIs were designed to selec- Corresponding Author: Forest M. White, Massachusetts Institute of Technology, tively target T790M and EGFR TKI-sensitizing mutations over the 77 Mass Avenue, Room 76-353F, Cambridge, MA 02139. Phone: 617-258-8949; wild-type receptor. Recently, one of these, the irreversible TKI Fax: 617-258-0225; E-mail: [email protected] osimertinib, received FDA approval for advanced NSCLC by doi: 10.1158/1535-7163.MCT-17-0413 showing promising clinical efficacy (6, 13). However, despite Ó2017 American Association for Cancer Research. significant increase in progression-free survival with osimertinib 2572 Mol Cancer Ther; 16(11) November 2017 Downloaded from mct.aacrjournals.org on September 25, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst August 22, 2017; DOI: 10.1158/1535-7163.MCT-17-0413 Proteomics of In Vivo Resistance to EGFR-Targeted Therapy as compared with platinum-pemetrexed in T790M-expressing Cell culture and engineered cell lines NSCLC patients, development of resistance still limited the effi- Human NSCLC cell lines H1975 and HCC827 were obtained cacy of this treatment (7, 14). from the ATCC. The engineered H1975-HGF cell line was derived Given the challenge of therapy resistance, there have been from H1975 to constitutively express the human HGF gene as considerable efforts over the past decade to define resistance described previously (24). The HCC827-ER1 cell line was derived mechanisms at a molecular level. In this respect, it has become from HCC827 to harbor MET amplification, which was assessed clear that resistance does not merely evolve around the targetable by quantitative PCR relative to RNase P (Crown Bioscience UK). driver of disease as exemplified by EGFR T790M. A recurrent DR-HCC827 was a kind gift from Allison Claas and Douglas theme involves the additional engagement of bypass signaling Lauffenburger at MIT (Cambridge, MA) and developed as a pathways driven by other receptor tyrosine kinases (RTK) to drug-resistant (DR) clone from HCC827 after continuous treat- support tumor cell growth and survival (15). For instance, mul- ment with erlotinib. Cell lines for in vitro studies were received tiple studies have highlighted activation of hepatocyte growth in 2016 and were used with no further authentication or myco- factor receptor (Met), by increased expression of the receptor due plasma testing. to MET gene amplification or by increased expression of the ligand Cell lines were maintained in RPMI1640 medium supplemen- hepatocyte growth factor (HGF), as an important resistance ted with 10% heat-inactivated FBS (Gibco), 2 mmol/L L-gluta- mechanism to both first- and third-generation EGFR TKIs mine (Gibco), and 1% penicillin/streptomycin (Gibco). For (9, 11, 16–18). Other RTK-mediated resistance mechanisms H1975-HGF cells, 2 mg/mL puromycin (Sigma) were added to include activation of human EGFR 2 (HER2), insulin-like growth the medium. Cells were cultured in a humidified incubator at factor 1 receptor (IGF1R), and Axl (19–21). The frequent occur- 37 C in an atmosphere of 5% CO2. rence of bypass signaling resistance suggests the need for an approach whereby cotargeting multiple pathways could serve as In vivo tumor models a strategy to delay or overcome resistance. Bispecific antibodies Animal studies were performed at Charles River Discovery present one such approach, and have recently been approved in Services and Crown Bioscience Inc. All procedures relating to leukemia, with several other bispecific antibodies in advanced animal care, handling, and treatment in this article were per- clinical development (22, 23). For NSCLC, the novel bispecific formed according to the guidelines approved by Institutional antibody JNJ-61186372 targeting EGFR and Met was recently Animal Care and Use Committee. In brief, H1975/H1975-HGF reported to be effective in EGFR TKI–resistant preclinical models cells (5 Â 106) and HCC827/HCC827-ER1 cells (5 Â 106 with (24, 25). However, even in the context of this promising preclin- Matrigel) were injected subcutaneously into the flanks of female ical data, multiple tumor xenografts in mouse models continued CD1 nu/nu mice (4–6 weeks old; Charles River Laboratories) and to grow out in the presence of JNJ-61186372, suggesting that BALB/c nude mice (6–8 weeks old; Crown Bioscience Inc.), acquired resistance will most likely represent a clinical challenge, respectively. Treatment began when tumors were established and even for bispecific antibody treatments. volume reached approximately 400–600 mm3. Osimertinib was Knowing that NSCLC patients inevitably experience repeated administered once per day by oral gavage at a dose of 5 mg/kg. JNJ- relapses due to acquired resistance, the targeted options of 61186372 was administered by intraperitoneal injection biweek- current FDA-approved therapies for these patients
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