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

Author Manuscript Published OnlineFirst on July 30, 2013; DOI: 10.1158/1541-7786.MCR-13-0228 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Perspective

Unintentional weakness of cancers: the MEK/ERK pathway as a double-edged sword

Kenichi Suda1, 2, and Tetsuya Mitsudomi1

1Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of

Medicine, Osaka-Sayama; 2Department of Surgery and Science, Graduate School of

Medical Sciences, Kyushu University, Fukuoka, JAPAN.

Running title: Treat “drug addicted” cancers

Keywords: molecular target therapy, oncogenic mutations, acquired resistance, drug

dependency, MEK/ERK pathway

Financial support: This study is supported in part by a Grant-in-Aid for Scientific

Research (B) from the Japan Society for the Promotion of Science (25830119).

Correspondence and address reprint requests to: Kenichi Suda, M.D.,

Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of

Medicine, 377-2 Ohno-Higashi, Osaka-Sayama 589-8511, Japan

Downloaded from mcr.aacrjournals.org on September 27, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 30, 2013; DOI: 10.1158/1541-7786.MCR-13-0228 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Tel: +81-72-366-0221; Fax: +81-72-367-7771;

E-mail: [email protected]

Disclosure of Potential Conflict of Interest: Dr. Mitsudomi has received speaker’s

bureau from AstraZeneca, Chugai, Pfizer, and Boehringer-Ingelheim and received

consultation fees from AstraZeneca, Chugai, Roche, Boehringer-Ingelheim, Pfizer,

and Clovis Oncology. Dr. Suda declares no conflict of interest.

Summary

Recent advances in molecular target therapy have greatly improved treatment

outcomes for cancers driven by oncogenic mutations. However despite initial

dramatic responses, cancer cells eventually acquire resistance to these drugs,

showing flexible and diverse responses. Interestingly, cancer cells may sometimes

over-adapt to the environment with the drug, leading to a state in which cancer cells

cannot survive without the drug. This interesting phenomenon, which can be termed

as “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. By

comparing these two preclinical models, we noticed intriguing parallels of “drug

addicted” cancers: (a) overexpression of driver oncogenes as causes of acquired

resistance; (b) overexpression of driver oncogenes causing MEK-ERK

hyperactivation under drug free conditions; (c) hyperactivation of the MEK-ERK

pathway as critical to this “drug addiction” phenomenon; (d) ongoing dependence on

the driver oncogene; and (e) morphological changes in resistant cells under drug-free

conditions. In this perspective article, we focus on this interesting and weird

phenomenon and discuss treatment strategies to utilize this unintentional weakness

of cancers.

(185 words)

Introduction

Recent advances in molecular oncology have identified several pairs of

oncogene-dependent cancers and their molecular target drugs. These include

chronic myelogenous leukemia with BCR-ABL fusion (imatinib [1], dasatinib, nilotinib,

bosutinib, or ponatinib [2]); gastrointestinal stromal tumors with c-KIT mutation

(imatinib or sunitinib); lung adenocarcinomas with epidermal growth factor receptor

(EGFR) mutation (gefitinib [3, 4]), erlotinib [5] or afatinib [6]); lung adenocarcinoma

with anaplastic lymphoma kinase fusion (crizotinib) (7); and melanoma with BRAF

mutation (vemurafenib [8] or dabrafenib [9]). Although these drugs are initially very

effective for their respective cancers, emergence of resistance is inevitable.

Background on acquired resistance

As cancer cells show flexible and diverse responses to anti-cancer drugs (10, 11),

many mechanisms of acquired resistance have been reported. These mechanisms

can be classified into two groups: (i) alterations of oncogenic drivers themselves, and

(ii) activation of alternative cell-growth / anti-apoptotic signalling pathways that bypass

inhibited oncogenic driver signalling. Alterations of oncogenic drivers themselves

include secondary drug resistant mutations (12–14) and overexpression or

amplification of the oncogenic drivers (15–17).

To avoid or delay emergence of acquired resistance, clinicians usually use continuous

treatment with these drugs. From a commonsense point of view, discontinuation of

drug treatment may give cancer cells chance to survive and to acquire resistance to

the drug of interest. Furthermore, this practice leads to the concept of “disease flare”

phenomenon—explosive re-growth of tumors after withdrawal of the molecular target

drug due to progressive disease (PD), which encourages the strategy to continue the

drug even after the patient acquires resistance (beyond PD).

“Drug addiction” phenomenon in preclinical acquired resistant models

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 to the drug environment. However, these resistance mechanisms

sometimes result in over-adaptation to the environment with the drug, leading to a

state in which cancer cells are unable to survive without the drug. This interesting

phenomenon, which can be termed as “drug dependency” or “drug addiction,” is

exemplified in preclinical acquired-resistance models of BRAF-mutated melanoma

treated with vemurafenib (18) and EGFR-mutated lung cancer treated with EGFR

tyrosine kinase inhibitors (TKI) (16).

To find the molecular characteristics of cancers with “drug addiction,” we compared

these two preclinical models and noticed intriguing parallels (Figure 1):

(a) overexpression of driver oncogenes as causes of acquired resistance;

(b) overexpression of driver oncogenes causing MEK-ERK hyperactivation under

drug-free conditions; (c) hyperactivation of the MEK-ERK pathway as critical to this

“drug addiction” phenomenon; (d) ongoing dependence on the driver oncogene (i.e.,

resistant cells killed by high concentrations of the molecular target drug); and

(e) morphological changes in resistant cells under drug-free conditions.

The RAS-RAF-MEK-ERK pathway is known to promote cell proliferation. Why does

hyperactivation of this pathway cause the “drug addiction” phenomenon? One clue is

the bilateral character of the RAS-RAF-MEK-ERK pathway: several reports observed

that hyperactivation of this pathway caused senescence or growth arrest (19–21). 5

Actually, a part of our “EGFR-TKI addicted” cells showed positive staining for

senescence-associated beta-galactosidase under drug-free conditions (16).

Mathematical modelling and experimental validation has shown the RAF-MEK-ERK

pathway to be a negative feedback amplifier (NFA) (22): activated ERK suppresses

activation of upstream molecules as negative feedback loops. Considering that a

hyperactivated MEK-ERK pathway perturbs growth of cancer cells, this NFA system

may fail in “drug addicted” cancer cells. Because the MEK-ERK pathway is an

important downstream signal for many oncogenic drivers, the concept of “drug

addiction” acquired with drug resistance might apply to a wide range of cancer types.

Use of “drug addiction” in cancer treatment

If this “drug addiction” phenomenon exists in actual patients, how we can treat “drug

addicted” cancers, or suppress emergence of acquired resistance related to such

“drug addiction”? The easiest answer is to stop administering the drug in question if

clinicians identify the above characteristics of “drug addiction” in cancer specimens

after resistance to the drug occurs. However this strategy may not work over the long

term; our “EGFR-TKI addicted” cancer cells started to re-grow under drug-free

conditions a month after the cessation of EGFR-TKI exposure (16). Cancer cells that

returned from the “drug addicted” state showed decreased EGFR expression but

retained moderate resistance to EGFR-TKI.

Another means of suppressing emergence of acquired resistance related to “drug

addiction” is the discontinuous treatment strategy (18, 23). Thakur et al. showed

significant survival advantage from an intermittent dosing schedule for vemurafenib

(4 weeks on drug/2 weeks off drug) compared with continuous dosing (18). This

treatment schedule may also decrease adverse drug effects. However, whether all

cancers can be treated with this intermittent dosing schedule is unclear. If not,

identification of pre-treatment biomarkers that can distinguish cancers suitable for

intermittent dosing is desired to avoid cancer “flare” due to drug cessation (24).

The third candidate strategy is the intermittent high-dose pulse of molecular target

drug in conjunction with continuous low-dose administration as suggested by

Chmielecki and colleagues (25). This strategy was originally developed to optimize

dosing of EGFR-TKI for EGFR mutated lung adenocarcinoma, based on

characteristics of T790M mutated (secondary drug resistant mutation) cancer cells

that showed slower cell growth compared with drug-sensitive parent cells.

Considering the characteristics of “drug-addicted” cancer cells to show ongoing

dependence on the driver oncogene, intermittent high-dose pulse of molecular target

drug in conjunction with a continuous low-dose administration can be effective to kill

“drug-addicted” cancer cells, preventing cancer “flare.”

Conclusion

Molecular target drugs have changed conventional wisdom about anti-cancer drugs

and treatment strategies for cancers with known oncogenic drivers. Further

exploration of molecular mechanisms in this area may also uncover unanticipated

characteristics of these cancers.

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Figure legend

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.

Figure 1

Unintentional weakness of cancers: the MEK/ERK pathway as a double-edged sword

Kenichi Suda and Tetsuya Mitsudomi

Mol Cancer Res Published OnlineFirst July 30, 2013.

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