Unintentional Weakness of Cancers: the MEK–ERK Pathway As a Double-Edged Sword

Published OnlineFirst July 30, 2013; DOI: 10.1158/1541-7786.MCR-13-0228

Molecular Cancer Perspective Research

Unintentional Weakness of Cancers: The MEK–ERK Pathway as a Double-Edged Sword

Kenichi Suda1,2 and Tetsuya Mitsudomi1

Summary Recent advances in molecular targeted therapies have greatly improved treatment outcomes for cancers driven by oncogenic mutations. Despite initial and dramatic clinical responses, tumors eventually acquire resistance to these targeted therapies, showing ﬂexible and diverse responses. Interestingly, cancer cells sometimes overadapt to the drug treatment environment, leading to a state in which cancer cells cannot survive without the drug. This interesting phenomenon (often called "drug dependency" or "drug addiction") is exempliﬁed in preclinical acquired resistance models of BRAF-mutated melanoma treated with vemurafenib and EGFR-mutated lung cancer treated with EGFR tyrosine kinase inhibitors. A number of intriguing parallels in drug-addicted cancers became apparent in a comparison of the two models: (i) overexpression of driver oncogenes as causes of acquired resistance; (ii) overexpression of driver oncogenes causing MEK–ERK hyperactivation under drug-free conditions; (iii) hyperactivation of the MEK–ERK pathway as critical to this drug addiction phenomenon; (iv) ongoing dependence on the oncogenic driver; and (v) morphologic changes in resistant cells under drug-free conditions. This Perspective article not only focuses on this interesting and peculiar phenomenon but also discusses weapon strategies to exploit this unintentional weakness of cancers. Mol Cancer Res; 11(10); 1125–8. 2013 AACR.

Introduction themselves, and (ii) activation of alternative cell-growth/ Recent advances in molecular oncology have identified antiapoptotic signaling pathways that bypass inhibited several pairs of oncogene-dependent cancers and their oncogenic driver signaling. Alterations of oncogenic dri- molecular target drugs. These include chronic myelogenous vers themselves include secondary drug-resistant muta- BCR-ABL tions (12–14) and overexpression or amplification of the leukemia with fusion [(imatinib; ref. 1) and – (dasatinib, nilotinib, bosutinib, or ponatinib; ref. 2)]; gas- oncogenic drivers (15 17). trointestinal stromal tumors with c-KIT mutation (imatinib To avoid or delay emergence of acquired resistance, or sunitinib); lung adenocarcinomas with EGF receptor clinicians usually use continuous treatment with these drugs. (EGFR) mutation [(gefitinib; refs. 3, 4), (erlotinib; ref. 5), From a commonsense point of view, discontinuation of drug or (afatinib; ref. 6)]; lung adenocarcinoma with anaplastic treatment may give cancer cells a chance to survive and to lymphoma kinase fusion (crizotinib; ref. 7); and melanoma acquire resistance to the drug of interest. Furthermore, this BRAF practice leads to the concept of "disease flare" phenome- with mutation [(vemurafenib; ref. 8) or (dabrafenib; — ref. 9)]. Although these drugs are initially very effective for non explosive regrowth of tumors after withdrawal of the their respective cancers, emergence of resistance is inevitable. molecular target drug due to progressive disease (PD), which encourages the strategy to continue the drug even after the Background on acquired resistance patient acquires resistance (beyond PD). As cancer cells show flexible and diverse responses to anticancer drugs (10, 11), many mechanisms of acquired "Drug addiction" phenomenon in preclinical acquired resistance have been reported. These mechanisms can be resistance models classified into two groups: (i) alterations of oncogenic drivers However, interestingly, the opposite may also be true in some patients treated with molecular target drugs. Molecular aberrations that confer resistance enable cancer cells to adapt Authors' Affiliations: 1Division of Thoracic Surgery, Department of Sur- to the drug environment. However, these resistance mechan- gery, Kinki University Faculty of Medicine, Osaka-Sayama; and 2Depart- isms sometimes result in overadaptation to the environment ment of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan with the drug, leading to a state in which cancer cells are unable to survive without the drug. This interesting phe- Corresponding Author: Kenichi Suda, Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 nomenon, which can be termed as "drug dependency" or Ohno-Higashi, Osaka-Sayama 589-8511, Japan. Phone: 81-72-366- "drug addiction", is exemplified in preclinical acquired- 0221; Fax: 81-72-367-7771; E-mail: [email protected] resistance models of BRAF-mutated melanoma treated with doi: 10.1158/1541-7786.MCR-13-0228 vemurafenib (18) and EGFR-mutated lung cancer treated 2013 American Association for Cancer Research. with EGFR tyrosine kinase inhibitors (TKI; ref. 16).

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Figure 1. Schema of changes in EGFR-mutated lung cancer (A) and BRAF-mutated melanoma (B) from "oncogene addiction" to "acquired resistance," and further to "drug addiction" in response to EGFR–TKI and vemurafenib, respectively.

To ﬁnd the molecular characteristics of cancers with as negative feedback loops. Considering that a hyperacti- "drug addiction", we compared these two preclinical vated MEK–ERK pathway perturbs growth of cancer cells, models and noticed intriguing parallels (Fig. 1): (i) over- this NFA system may fail in "drug-addicted" cancer cells. expression of driver oncogenes as causes of acquired Because the MEK–ERK pathway is an important down- resistance; (ii) overexpression of driver oncogenes causing stream signal for many oncogenic drivers, the concept of MEK–ERK hyperactivation under drug-free conditions; "drug addiction" acquired with drug resistance might apply (iii) hyperactivation of the MEK–ERK pathway as critical to a wide range of cancer types. to this "drug addiction" phenomenon; (iv) ongoing dependence on the driver oncogene (i.e., resistant cells killed by Use of "drug addiction" in cancer treatment high concentrations of the molecular target drug); and If this "drug addiction" phenomenon exists in actual (v) morphologic changes in resistant cells under drug-free patients, how we can treat "drug-addicted" cancers, or conditions. suppress emergence of acquired resistance related to such The RAS–RAF–MEK–ERK pathway is known to pro- "drug addiction"? The easiest answer is to stop administering mote cell proliferation. Why does hyperactivation of this the drug in question if clinicians identify the above char- pathway cause the "drug addiction" phenomenon? One clue acteristics of "drug addiction" in cancer specimens after is the bilateral character of the RAS–RAF–MEK–ERK resistance to the drug occurs. However, this strategy may pathway: several reports observed that hyperactivation of not work over the long term; our "EGFR–TKI–addicted" this pathway caused senescence or growth arrest (19–21). cancer cells started to regrow under drug-free conditions a Actually, a part of our "EGFR-TKI-addicted" cells showed month after the cessation of EGFR–TKI exposure (16). positive staining for senescence-associated b-galactosidase Cancer cells that returned from the "drug-addicted" state under drug-free conditions (16). Mathematical modeling showed decreased EGFR expression but retained moderate and experimental validation has shown the RAF–MEK– resistance to EGFR–TKI. ERK pathway to be a negative feedback ampliﬁer (NFA; 22): Another means of suppressing emergence of acquired activated ERK suppresses activation of upstream molecules resistance related to "drug addiction" is the discontinuous

1126 Mol Cancer Res; 11(10) October 2013 Molecular Cancer Research

Treat "Drug-Addicted" Cancers

treatment strategy (18, 23). Thakur and colleagues showed Conclusion fi signi cant survival advantage from an intermittent dosing Molecular target drugs have changed conventional wis- schedule for vemurafenib (4 weeks on drug/2 weeks off drug) dom about anticancer drugs and treatment strategies for compared with continuous dosing (18). This treatment cancers with known oncogenic drivers. Further exploration schedule may also decrease adverse drug effects. However, of molecular mechanisms in this area may also uncover whether all cancers can be treated with this intermittent unanticipated characteristics of these cancers. dosing schedule is unclear. If not, identification of pretreat- ment biomarkers that can distinguish cancers suitable for fl fl Disclosure of Potential Con icts of Interest intermittent dosing is desired to avoid cancer " are" due to Dr. T. Mitsudomi received honoraria from the speaker's bureau of AstraZeneca, drug cessation (24). Chugai, Pfizer, and Boehringer–Ingelheim and is a consulant/advisory board member of AstraZeneca, Chugai, Roche, Boehringer–Ingelheim, Pfizer, and Clovis Oncology. The third candidate strategy is the intermittent high- No potential conflicts of interest was disclosed by the other author. dose pulse of molecular target drug in conjunction with continuous low-dose administration as suggested by Authors' Contributions Chmielecki and colleagues (25). This strategy was orig- Conception and design: K. Suda inally developed to optimize dosing of EGFR–TKI for Acquisition of data (provided animals, acquired and managed patients, provided EGFR facilities, etc.): K. Suda -mutated lung adenocarcinoma, on the basis of Analysis and interpretation of data (e.g., statistical analysis, biostatistics, compu- characteristics of T790M-mutated (secondary drug-resis- tational analysis): K. Suda tant mutation) cancer cells that showed slower cell growth Writing, review, and/or revision of the manuscript: K. Suda, T. Mitsudomi Administrative, technical, or material support (i.e., reporting or organizing data, compared with drug-sensitive parent cells. Considering constructing databases): K. Suda the characteristics of "drug-addicted" cancer cells to show Study supervision: K. Suda, T. Mitsudomi ongoing dependence on the driver oncogene, intermittent high-dose pulse of molecular target drug in conjunction Grant Support This work is supported in part by a Grant-in-Aid for Scientific Research (B) from with a continuous low-dose administration can be effec- the Japan Society for the Promotion of Science (grant no. 25830119). tive to kill "drug-addicted" cancer cells, preventing cancer "flare." Received May 3, 2013; accepted July 5, 2013; published OnlineFirst July 30, 2013.

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1128 Mol Cancer Res; 11(10) October 2013 Molecular Cancer Research

Unintentional Weakness of Cancers: The MEK−ERK Pathway as a Double-Edged Sword

Kenichi Suda and Tetsuya Mitsudomi

Mol Cancer Res 2013;11:1125-1128. Published OnlineFirst July 30, 2013.

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