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Addiction to Multiple Oncogenes Can Be Exploited to Prevent the Emergence of Therapeutic Resistance

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Addiction to Multiple Oncogenes Can Be Exploited to Prevent the Emergence of Therapeutic Resistance Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance Peter S. Choi, Yulin Li, and Dean W. Felsher1 Division of Oncology, Departments of Medicine, Pathology, and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305 Edited by Stephen R. Hann, Vanderbilt University, Nashville, TN, and accepted by the Editorial Board July 2, 2014 (received for review April 2, 2014) Many cancers exhibit sensitivity to the inhibition of a single genetic therapy for cancer, it has been proposed that a similar strategy, lesion, a property that has been successfully exploited with using combinations directed against multiple dependencies, is the oncogene-targeted therapeutics. However, inhibition of single most likely to prevent resistance (7). Indeed, mathematical mod- oncogenes often fails to result in sustained tumor regression due eling indicates that targeting at least two independently re- to the emergence of therapy-resistant cells. Here, we report that quired pathways may be sufficient to prevent tumor recurrence MYC-driven lymphomas frequently acquire activating mutations in (15). However, there exists little experimental evidence directly β-catenin, including a previously unreported mutation in a splice testing such an approach and it remains unclear which com- acceptor site. Tumors with these genetic lesions are highly depen- binations of targets would be most effective at inducing long- dent on β-catenin for their survival and the suppression of β-catenin term remissions. resulted in marked apoptosis causally related to a decrease in Bcl-xL MYC is one of the most frequently amplified oncogenes in expression. Using a novel inducible inhibitor of β-catenin, we illus- human cancer (16). In the Eμ-tTA/tetO-MYC conditional mouse trate that, although MYC withdrawal or β-catenin inhibition alone model, overexpression of MYC results in the development of results in initial tumor regression, most tumors ultimately re- aggressive T-cell lymphoma, and MYC inactivation in estab- curred, mimicking the clinical response to single-agent targeted lished tumors is sufficient to induce tumor regression through therapy. Importantly, the simultaneous combined inhibition of processes such as proliferative arrest, cellular senescence, apo- β both MYC and -catenin promoted more rapid tumor regression ptosis, and the shutdown of angiogenesis (17–19). The extent of and successfully prevented tumor recurrence. Hence, we demon- regression is dependent on both cell-intrinsic and host-dependent β strated that MYC-induced tumors are addicted to mutant -catenin, contexts, and in particular, tumors frequently recur following β and the combined inactivation of MYC and -catenin induces sus- MYC inactivation in the absence of an intact adaptive immune tained tumor regression. Our results provide a proof of principle system (20). Recurring tumors restore expression of the MYC that targeting multiple oncogene addicted pathways can prevent transgene or up-regulate expression of endogenous Myc,dem- therapeutic resistance. onstrating that resistance occurs primarily through reactivation of the MYC pathway (21). Thus, MYC oncogene addiction and oncogene addiction | combination targeted therapy | splice site mutations tumor recurrence in the Eμ-tTA/tetO-MYC lymphoma model resembles the clinical course of human cancers treated with single ancer cells are highly sensitive to the targeted inhibition of agent targeted therapy. Csingle driver mutations, eliciting a phenomenon known as Here, we demonstrate that the combined inactivation of two “ ” oncogene addiction (1). The identification of genetic dependencies oncogene addiction pathways can result in sustained tumor re- in multiple tumor types has resulted in the development of sev- gression. Moreover, we describe a previously unidentified splice eral molecularly targeted therapeutics, including the BCR-ABL acceptor site mutation in β-catenin that is associated with MYC- kinase inhibitor imatinib for the treatment of chronic myeloge- induced lymphomagenesis. Tumors with mutations in β-catenin nous leukemia (CML), the EGFR kinase inhibitor gefitinib for – the treatment of non small cell lung cancer (NSCLC), and the Significance BRAF kinase inhibitor vemurafenib for the treatment of advanced melanoma (2–4). Although these oncogene-targeted agents have provided promising clinical responses, many patients ultimately The rationale of targeting specific genetic dependencies for the experience a recurrence of their disease due to the development of treatment of cancer has been validated by the promising clin- drug resistance (4–6). Thus, it has become evident that mono- ical responses obtained with oncogene-targeted therapies. therapy with targeted drugs is insufficient for achieving sustained However, in most cases, the development of resistance remains a major obstacle toward achieving long-term or complete dis- tumor regression. ease remission. Here, we identified mutant β-catenin as a com- Resistance to targeted therapy can arise through multiple mech- mon secondary oncogene addiction pathway in MYC-addicted anisms, depending on the tumor type and the targeted oncogenic lymphoma. We demonstrate that, although withdrawal or pathway (7). Cells frequently acquire resistance through mutations inhibition of either oncogene is sufficient to induce initial in the targeted oncogene itself that disrupt drug binding, as in the tumor regression, only combined inhibition of both oncogene case of BCR-ABL and EGFR (8, 5, 6). In addition, resistance to addiction pathways results in sustained tumor regression. Our EGFR inhibition in NSCLC and BRAF inhibition in melanoma results suggest clinical outcomes can be dramatically improved has been found to occur through a variety of mechanisms that through the simultaneous targeted inhibition of multiple onco- activate downstream signaling proteins or alternative pathways, genic addiction pathways. which can functionally substitute for loss in activity of the targeted – oncogene (9 11). Although significant progress has been made Author contributions: P.S.C., Y.L., and D.W.F. designed research; P.S.C. and Y.L. performed in the identification and inhibition of resistance pathways, it may research; P.S.C. and Y.L. analyzed data; and P.S.C. and D.W.F. wrote the paper. prove challenging to anticipate and suppress all of the potential The authors declare no conflict of interest. mechanisms of resistance for each oncogene-addicted cancer and This article is a PNAS Direct Submission. S.R.H. is a guest editor invited by the Editorial targeted therapeutic agent. Board. Combination therapy has been successfully applied to prevent 1To whom correspondence should be addressed. Email: [email protected]. resistance in the treatment of infectious diseases such as HIV This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (12, 13) and tuberculosis (14). In the context of oncogene-targeted 1073/pnas.1406123111/-/DCSupplemental. E3316–E3324 | PNAS | Published online July 28, 2014 www.pnas.org/cgi/doi/10.1073/pnas.1406123111 Downloaded by guest on September 27, 2021 PNAS PLUS A B Cooperating driver β-catenin mutations mutations MYC overexpression 7/30 None ??? Missense 19/30 tTA ??? T-cell lymphoma 4/30 Splice-site tetO MYC ??? C Primary lymphomas Lymphoma-derived cell lines Tumor ID: Thymus B6678 B6422 B6680 B7647 C1194 C1296 C1369 C1497 C1630 C3598 D0290 C1194 C1571 C1573 B3470 B3760 B4329 B4334 β-catenin β-catenin status: WT WTT41A WT G34R Δex3 D32N WT WT WT WT Δex3 Δex3 WT WT Δex3 Δex3 Δex3 T41A β-actin D E β-catenin primary transcript β-catenin protein splice donor splice acceptor NH2 Exon3 COOH Exon1 GU AG Exon2 GU AG Exon3 GU AG Exon4 Armadillo repeats Transactivation domain 33 37 41 45 ...SYLDSGIHSGATTTAPSLSGK... wildtype transcript Exon1 Exon2 Exon3 Exon4 P P P P D32N mutation T41A mutation Δexon3 transcript Exon1 Exon2 Exon4 31 32 33 40 41 42 Leu Asp Asn Ser Thr Thr Ala Thr Splice acceptor mutation 1 Splice acceptor mutation 2 splice splice acceptor Exon3 acceptor Exon3 * * T TTGG/AA TTC A CCA/G CCAAC * * TTA C A/G G C T G TTA C G/AA C T G F MYC Axin2 Enc1 10 1000 1000 ** ** 100 100 1 10 10 MEDICAL SCIENCES 1 1 Relative expression Relative expression Relative expression 0.1 0.1 0.1 β-catenin β-catenin β-catenin β-catenin β-catenin β-catenin wildtype mutant wildtype mutant wildtype mutant Fig. 1. MYC-induced lymphomas frequently harbor stabilizing mutations in β-catenin. (A)InEμ-tTA/tetO-MYC transgenic mice, T-cell lymphomas are pro- posed to arise as a result of MYC overexpression and alterations in unidentified cooperating pathways. (B) Distribution of β-catenin mutations detected by sequencing of DNA from Eμ-tTA/tetO-MYC primary lymphoma specimens. (C) Western blot analysis for β-catenin protein in primary MYC-induced lymphomas and lymphoma-derived cell lines. β-actin is shown as a loading control. Closed and open triangles denote full-length and Δexon3 β-catenin protein, re- spectively. Tumors with mutant β-catenin are labeled in red. (D) Schematic of β-catenin depicting the phosphorylation residues encoded by exon 3 that are critical for protein degradation. Also shown are sequence chromatograms of mutations in phosphorylation residues identified in primary MYC-induced lymphomas. (E) Diagram of conserved splice donor and acceptor sites required for proper splicing of the β-catenin primary transcript. Also shown are se- quence chromatograms of splice acceptor site mutations identified in primary MYC-induced
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