The Increasing Dominance of Teams in Production of Knowledge

Abstract

We have used 19.9 million papers over 5 decades and 2.1 million patents to demonstrate that teams increasingly dominate solo authors in the production of knowledge. Research is increasingly done in teams across nearly all fields. Teams typically produce more frequently cited research than individuals do, and this advantage has been increasing over time. Teams now also produce the exceptionally high-impact research, even where that distinction was once the domain of solo authors. These results are detailed for sciences and engineering, social sciences, arts and humanities, and patents, suggesting that the process of knowledge creation has fundamentally changed.

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DOI: 10.1126/science.1136099
, 1036 (2007); 316Science
et al.Stefan Wuchty,
of Knowledge
The Increasing Dominance of Teams in Production
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References and Notes
1. G. G. Simpson, C. Dean, Science 296, 285 (2002).
2. L. Corbesier, G. Coupland, Plant Cell Environ. 28,54
(2005).
3. T. Imaizumi, S. A. Kay, Trends Plant Sci. 11, 550 (2006).
4. B. Thomas, D. Vince-prue, Photoperiodism in Plants
(Academic Press, London, 1997).
5. Y. Kobayashi, H. Kaya, K. Goto, M. Iwabuchi, T. Araki,
Science 286, 1960 (1999).
6. I. Kardailsky et al., Science 286, 1962 (1999).
7. S. Takada, K. Goto, Plant Cell 15, 2856 (2003).
8. H. An et al., Development 131, 3615 (2004).
9. M. Abe et al., Science 309, 1052 (2005).
10. P. A. Wigge et al., Science 309, 1056 (2005).
11. J. A. D. Zeevaart, Plant Cell 18, 1783 (2006).
12. E. Lifschitz et al., Proc. Natl. Acad. Sci. U.S.A. 103, 6398
(2006).
13. H. Böhlenius, S. Eriksson, F. Parcy, O. Nilsson, Science
316, 367 (2007).
14. T. Izawa et al., Genes Dev. 16, 2006 (2002).
15. S. Kojima et al., Plant Cell Physiol. 43, 1096 (2002).
16. R. Hayama, S. Yokoi, S. Tamaki, M. Yano, K. Shimamoto,
Nature 422, 719 (2003).
17. R. Ishikawa et al., Plant Cell 17, 3326 (2005).
18. A. Guivarc'H, A. Spena, M. Noin, C. Besnard, D. Chriqui,
Transgen. Res. 5, 3 (1996).
19. T. Asano et al., Plant Cell Physiol. 43, 668 (2002).
20. R. Ando, H. Hama, M. Yamamoto-Hino, H. Mizuno,
A. Miyawaki, Proc. Natl. Acad. Sci. U.S.A. 99, 12651
(2002).
21. S. Arimura, J. Yamamoto, G. P. Aida, M. Nakazono,
N. Tsutsumi, Proc. Natl. Acad. Sci. U.S.A. 101, 7805
(2004).
22. P. Giavalisco, K. Kapitza, A. Kolasa, A. Buhtz, J. Kehr,
Proteomics 6, 896 (2006).
23. M. K. Chailakhyan, C. R. Acad. Sci. URSS 13, 79 (1936).
24. A. Lang, in Encyclopedia of Plant Physiology,
W. Ruhland, Ed. (Springer, Berlin, 1965), vol. 15,
pp. 1380–1536.
25. J. A. D. Zeevaart, Annu. Rev. Plant Physiol. 27, 321
(1976).
26. M. G. Muszynski et al., Plant Physiol. 142, 1523 (2006).
27. P. Teper-Bamnolker, A. Samach, Plant Cell 17, 2661 (2005).
28. H. Böhlenius et al., Science 312, 1040 (2006).
29. We thank J. Kyozuka (University of Tokyo) for advice on
the experiments and comments on the manuscript,
K. Kadowaki (NIAS, Tsukuba) for the RPP16 promoter,
H. Uchimiya (University of Tokyo) for the rolC promoter,
and members of the Laboratory of Plant Molecular
Genetics at NAIST for discussions. This research was
supported by Grants-in-Aid for Scientific Research on
Priority Areas of the Ministry of Education, Culture,
Sports, Science, and Technology of Japan (to K.S.).
Supporting Online Material
www.sciencemag.org/cgi/content/full/1141753/DC1
Materials and Methods
Figs. S1 to S3
References
26 February 2007; accepted 6 April 2007
Published online 19 April 2007;
10.1126/science.1141753
Include this information when citing this pap er.
The Increasing Dominance of
Teams in Production of Knowledge
Stefan Wuchty,
1
* Benjamin F. Jones,
2
* Brian Uzzi
1,2
*†
We have used 19.9 million papers over 5 decades and 2.1 million patents to demonstrate that teams
increasingly dominate solo authors in the production of knowledge. Research is increasingly done in
teams across nearly all fields. Teams typically produce more frequently cited research than individuals
do, and this advantage has been increasing over time. Teams now also produce the exceptionally high-
impact research, even where that distinction was once the domain of solo authors. These results are
detailed for sciences and engineering, social sciences, arts and humanities, and patents, suggesting that
the process of knowledge creation has fundamentally changed.
A
n acclaimed tradition in the history and
sociology of science emphasizes the role
of the individual genius in scientific dis-
covery (1, 2). This tradition focuses on guiding
contributions of solitary authors, such as Newton
and Einstein, and can be seen broadly in the tend-
ency to equate great ideas with particular names,
such as the Heisenberg uncertainty principle, Eu-
clidean geometry, Nash equilibrium, and Kantian
ethics. The role of individual contributions is also
celebrated through science’s award-granting in-
stitutions, like the Nobel Prize Foundation (3).
Several studies, however , have explored an
apparent shift in science from this individual-
based model of scientific advance to a teamwork
model. Building on classic work by Zuckerman
and Merton, many authors have established a
rising propensity for teamwork in samples of
research fields, with some studies going back a
century (4–7). For example, de Solla Price ex-
amined the change in team size in chemistry from
1910 to 1960, forecasting that in 1980 zero per-
cent of the papers would be written by solo au-
thors (8). Recently , Adams et al. established that
over time, tea mwork had increased across
broader sets of fields among elite U.S. research
universities (9). Nevertheles s, the breadth and
depth of this projected shift in manpower remains
indefinite, particularly in fields where the size of
experiments and capital investments remain
small, raising the question as to whether the
projected growth in teams is universal or
cloistered in specialized fields.
A shift toward teams also raises new ques-
tions of whether teams produce better science.
Teams may bring greater collective knowledge
and effort, but they are known to experience so-
cial network and coordination losses that make
them underperform individuals even in highly
complex tasks (10–12), as F. Scott Fitzgerald
concisely observed when he stated that “no grand
idea was ever born in a conference” (13). From
this viewpoint, a shift to teamwork may be a
costly phenomenon or one that promotes low-
impact science, whereas the highest-impact ideas
remain the domain of great minds working alone.
We studied 19.9 million research articles in
the Institute for Scientific Information (ISI) Web
of Science database and an additional 2.1 million
patent records. The W eb of Science data covers
research publications in science and engineering
since 1955, social sciences since 1956, and arts
and humanities since 1975. The patent data cover
all U.S. registered patents since 1975 (14). A team
was defined as having more than one listed author
(publications) or inventor (patents). Following the
ISI classification system, the uni verse of scientific
publications is divided into three main branches
and their constituent subfields: science and
engineering (with 171 subfields), social sciences
(with 54 subfields), and arts and humanities (with
27 subfields). The universe of U.S. patents was
treated as a separate category (with 36 subfields).
See the Supporting Online Material (SOM) text
for details o n these classifications.
For science and engineering, social sciences,
and patents, there has been a substantial shift
toward collective research. In the sciences, team
size has grown steadily each year and nearly
1
Northwestern Institute on Complexity (NICO), North-
western University, Evanston, IL 60208, USA.
2
Kellogg
School of Management, Northwestern University, Evanston,
IL 60208, USA.
*These authors contributed equally to this work.
†To whom correspondence should be addressed. E-mail:
uzzi@northwestern.edu
Table 1. Patterns by subfield. For the three broad ISI categories and for patents, we counted the
number (N) and percentage (%) of subfields that show (i) larger team sizes in the last 5 years
compared to the first 5 years and (ii) RTI measures larger than 1 in the last 5 years. We show RTI
measures both with and without self-citations removed in calculating the citations received. Dash
entries indicate data not applicable.
N
fields
Increasing
team size
RTI > 1
(with self-citations)
RTI > 1
(no self-citations)
N
fields
% N
fields
% N
fields
%
Science and engineering 171 170 99.4 167 97.7 159 92.4
Social sciences 54 54 100.0 54 100.0 51 94.4
Arts and humanities 27 24 88.9 23 85.2 18 66.7
Patents 36 36 100.0 32 88.9 ––
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doubled, from 1.9 to 3.5 authors per paper , over
45 years.
Shifts toward teamwork in science and en-
gineering have been suggested to follow from the
increasing scale, complexity , and costs of big
science. Surprisingly then, we find an equally
strong trend toward teamwork in the social sci-
ences, where these drivers are much less notable.
Although social scientists in 1955 wrote 17.5%
of their papers in teams, by 2000 they wrote
51.5% of their papers in teams, an increase
similar to that in sciences and engineering. Mean
team size has also grown each year. On average,
today’s social sciences papers are written in pairs,
with a continuing, positive trend toward larger
teams. Unlike the other areas of research, single
authors still produce over 90% of the papers in
the arts and humanities. Nevertheless, there is a
positive trend toward teams in arts and human-
ities (P < 0.001). Lastly , patents also show a
rising dominance of teams. Although these data
are on a shorter time scale (1975–200 0), there
was a similar annualized increase in the propen-
sity for teamwork. Average team size has risen
from 1.7 to 2.3 inventors per patent, with the
positive trend toward larger teams continuing.
The generality of the shift to teamwork is
captured in T able 1. In sciences and engineering,
99.4% of the 171 subfields have seen increased
teamwork. Meanwhile, 100% of the 54 subfields
in the social sciences, 88.9% of the 27 subfields in
the humanities, and 100% of the 36 subfields in
patenting have seen increased teamwork.
T rends for individual fields are presented in
table S1. In the sciences, areas like medicine,
biology, and physics have seen at least a doubling
in mean team size over the 45-year period. Sur-
prisingly , even mathematics, long thought the do-
main of the loner scientist and least dependent of
the hard sciences on lab scale and capital-intensive
equipment, showed a marked increase in the frac-
tion of work done in teams, from 19% to 57%,
with mean team size rising from 1.22 to 1.84. In
the social sciences, psychology, economics, and
political science show enormous shifts toward
teamwork, sometimes doubling or tripling the
propensity for teamwork. With regard to average
team size, psychology, the closest of the social
sciences to a lab science, has the highest growth
(75.1%), whereas political science has the lowest
(16.6%). As reflected in Fig. 1A, the humanities
show lower growth rates in the fraction of
publications done in teams, yet a tendency
toward increased teamwork is still observed. All
areas of patents showed a positive change in both
the fraction of papers done by teams and the team
size, with only small variations across the areas
of patenting, suggesting that the conditions
favoring teamwork in patenting are largely
similar across subfields.
Our measure of impact was the number of
citations each paper and patent receives, which
has been shown to correlate with research quality
(15–17) and is frequently used in promotion and
funding reviews (18). Highly cited work was
defined as receiving more than the mean number
of citations for a given field and year (19). Teams
produced more highly cited work in each broad
area of research and at each point in time.
To explore the relationship between team-
work and impact in more detail, we defined the
relative team impact (R TI) for a given time period
and field. R TI is the mean number of citations
received by team-authored work divided by the
mean number of citations received by solo-
authored work. A RTI greater than 1 indicates
that teams produce more highly cited papers than
solo authors and vice versa for R TI less than 1.
When RTI is equal to 1, there is no difference in
citation rates for team- and solo-authored papers.
In our data set, the average R TI was greater than
1 at all points in time and in all broad research
areas: sciences and engineering, social sciences,
humanities, and patents. In other words, there is a
broad tendency for teams to produce more highly
cited work than individual authors. Further, R TI
is rising with time. For example, in sciences and
engineering, team-authored papers received 1.7
times as many citations as solo-authored papers
in 1955 but 2.1 times the citations by 2000. Simi-
lar upward trends in relative team impact appear
in sciences and engineering, social science, and
arts and humanities and more weakly in patents,
although the trend is still upward (20). During the
early periods, solo authors received subst an t ial ly
more citations on average than teams in many
subfields, especially within sciences and engi-
neering (Fig. 2E) and social sciences (Fig. 2F).
By the end of the period, however, there are
almost no subfields in sciences and engineering
and social sciences in which solo authors typical-
ly receive more citations than teams. Table S1
details R TIs for major individual research areas,
indicating that teams currently have a nearly uni-
versal impact advantage. In a minority of cases,
RTIs declined with time (e.g., –34.4% in mathe-
matics and –25.7% in education), although even
here teams currently have a large advantage in
citations received (e.g., 67% more average cita-
tions in mathematics and 105% in education).
The citation advantage of teams has also been
increasing with time when teams of fixed size are
compared with solo authors. In science and engi-
neering, for example, papers with two authors
received 1.30 times more citations than solo au-
thors in the 1950s but 1.74 times more citations
in the 1990s. In general, this pattern prevails for
comparisons between teams of any fixed size
versus solo authors (table S4).
A possible challenge to the validity of these
observations is the presence of self-citations, giv-
en that teams have opportunities to self-cite their
work more frequently than a single author. To
address this, we reran the analysis with all self-
citations removed from the data set (21). We
found that removing self-citations can produce
modest decreases in the RTI measure in some
fields; for example, RTIs fell from 3.10 to 2.87 in
medicineand2.30to2.13inbiology(tableS1).
Thus, removing self-citations can reduce the R TI
by 5 to 10%, but the relative citation advantag e of
teams remains essentially intact.
Because the progress of knowledge may be
driven by a small number of key insights (22), we
further test whether the most extraordinary con-
cepts, results, and technologies are the province
of solitary scientists or teams. Pooling all papers
and patents within the four research areas, we
calculated the frequency distribution of citations
to solo-authored and team-authored work, com-
paring the first 5 years and last 5 years of our
data. If these distributions overlap in their right-
hand tails, then a solo-authored paper or patent is
just as likely as a team-authored paper or patent
to be extraordinarily highly cited.
Our results show that teams now dominate
the top of the citation distribution in all four re-
search domains (Fig. 3, A to D). In the early years,
a solo author in science and engineering or the
social sciences was more likely than a team to
receive no citations, but a solo author was also
more likely to garner the highest number of cita-
tions, that is, to have a paper that was singularly
influential. However, by the most recent period, a
team-authored paper has a higher probability of
being extremely highly cited. For example, a
team-authored paper in science and engineering
is currently 6.3 times more likely than a solo-
authored paper to receive at least 1000 citations.
Lastly, in arts and humanities and in patents, in-
dividuals were never more likely than teams to
produce more-influential work. These patterns al-
so hold when self-citations are removed (fig. S5).
Fig. 1. The growth of teams. These plots present changes over time in the fraction of papers and
patents written in teams (A) and in mean team size (B). Each line represents the arithmetic average
taken over all subfields in each year.
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Taken together, these results suggest two im-
portant facts about preeminent work in our obser-
vational periods. First, it never appeared to be the
domain of solo authors in arts and humanities and
in patents. Second, solo authors did produce the
papers of singular distinction in science and engi-
neering and social science in the 1950s, but the
mantle of extraordinarily cited work has passed
to teams by 2000.
Over our 5-decade sample period, the in-
creasing capital intensity of research may have
been a key force in laboratory sciences where the
growth in teamwork has been intensive (8), but it
is unlikely to explain similar patterns in mathe-
matics, economics, and sociology , where we
found that growth rates in team size have been
nearly as large. Since the 1950s, the number of
researchers has grown as well, which could
promote finer divisions of labor and more
collaboration. Similarly, steady growth in knowl-
edge may have driven scholars toward more
spec ial iz atio n, p ro mpt ing lar ger and more diverse
teams (7, 10). However, we found that teamwork
is growing nearly as fast in fields where the
number of researchers has grown relatively
slowly (see Supporting Online Material).
Declines in communication costs could make
teamwork less costly as well (9, 23). Shift-
ing authorship norms may have influenced co-
authorship trends in fields with extremely large
teams, such as biomedicine and high-energy phys-
ics (24, 25), and yet our results hold across diverse
fields in which norms for order of authorship,
existence of postdoctorates , and prevalence of
grant-based research differ substantially.
References and Notes
1. R. K. Merton, Science 159, 56 (1968).
2. P. J. Bowler, I. R. Morus, Making Modern Science:
A Historical Survey (Univ. of Chicago Press, Chicago,
2005).
3. J. F. English, The Economy of Prestige: Prizes, Awards,
and the Circulation of Cultural Value (Harvard Univ.
Press, Cambridge, MA, 2005).
4. R. Collins, The Sociology of Philosophies: A Global Theory
of Intellectual Change (Harvard Univ. Press, Cambridge,
MA, 1998).
5. D. Cronin, D. Shaw, K. La Barre, J. Am. Soc. Inf. Sci.
Technol. 54, 855 (2003).
6. H. Zuckerman, R. K. Merton, in The Sociology of Science,
R. K. Merton, N. Storer, Eds. (Univ. of Chicago Press,
Chicago, 1973), pp. 545–550.
7. B. F. Jones, Nal. Bur. Econ. Res. Work. Pap. Ser.,
no. 11360 (2005).
8. D. J. de Solla Price, Little Science, Big Science (Columbia
Univ. Press, New York, 1963).
9. J. J. Adams, G. Black, R. Clemmons, P. E. Stephan, Res.
Policy 34, 259 (2005).
10. R. Guimerà, B. Uzzi, J. Spiro, L. Amaral, Science 308,
697 (2005).
11. N. Babchuk, K. Bruce, P. George, Am. Sociol. 30,5
(1999).
12. K. Y. Williams, C. A. O'Reilly, in Research in
Organizational Behavior, B. Staw, R. Sutton, Eds.
(JAI Press, Greenwich, CT, 1998), vol. 20, pp. 77–140.
13. F. S. Fitzgerald, in The Crack Up, E. Wilson, Ed. (New
Directions, New York, 1993), p. 122.
14. B. H. Hall, A. B. Jaffe, M. Trajtenberg, Natl. Bur. Econ.
Res. Work. Pap. Ser., no. 8498 (2001).
15. M. Trajtenberg, Rand J. Econ. 21, 172 (1990).
16. B. H. Hall, A. B. Jaffe, M. Trajtenberg, Rand J. Econ. 36,
16 (2005).
Fig. 3. Exceptional research. Pooling all publications and patents within the four research
categories, we calculated frequency distributions of citations received. Separate distributions are
calculated for single authors and for teams, and the ratio is plotted. A ratio greater than
1 indicates that a team-authored paper had a higher probability of producing the given range of
citations than a solo-authored paper. Ratios are compared for the early period (first 5 years of
available data) and late period (last 5 years of available data) for each research category, sciences
and engineering (A), social sciences (B), arts and humanities (C), and patents (D).
Fig. 2. The relative impact of teams. (A to D) Mean team size comparing all papers and patents with
those that received more citations than average in the relevant subfield. (E to H) The RTI, which is the
mean number of citations received by team-authored work divided by the mean number of citations
received by solo-authored work. A ratio of 1 indicates that team- and solo-authored work have
equivalent impact on average. Each point represents the RTI for a given subfield and year, whereas the
black lines present the arithmetic average in a given year.
18 MAY 2007 VOL 316 SCIENCE www.sciencemag.org
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REPORTS
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17. D. W. Aksnes, J. Am. Soc. Inf. Sci. Technol. 57, 169
(2006).
18. N. S. Ali, H. C. Young, N. M. Ali, Libr. Rev. 45, 39 (1996).
19. Citations received were counted from publication year to
2006. Recent publications have smaller citation counts
because they have had less time to be cited, but this
effect is standardized when comparing team versus solo
publications within a given year.
20. In patenting, we may observe weaker trends because (i)
citing earlier work can limit a patent’s scope, so that
applicants may avoid citations, and (ii) patent examiners
typically add the majority of citations, which makes
patent citations different from paper citations (26, 27).
21. A self-citation is defined as any citation where a common
name exists in the authorship of both the cited and the
citing papers. All citations were removed in which a citing
and cited author’s first initial and last name matched.
This method can also eliminate citations where the
authors are different people but share the same name.
However, performing Monte Carlo simulations on the
data, we find that such errors occur in less than 1 of
every 2000 citations. Thus, any errors introduced by this
method appear negligible. We did not remove self-
citations from patents because citations to previous work
in the patent literature are primarily assigned by the
patent examiner (27), who independently assigns
citations to earlier work based on the relevance of
previous patents’ content.
22. T. S. Kuhn, The Structure of Scientific Revolutions (Univ.
of Chicago Press, Chicago, 1970).
23. G. Becker, K. Murphy, Q. J. Econ. 107, 1137 (1992).
24. J. Drenth, JAMA 280, 219 (1998).
25. B. Cronin, J. Am. Soc. Inf. Sci. Technol. 52, 558
(2001).
26. B. Sampat, “Determinants of patent quality: An empirical
analysis” (Columbia Univ., New York, 2005).
27. J. Alcacer, M. Gittelman, Rev. Econ. Stat. 88, 774 (2006).
28. We thank R. Guimera, S. Stern, K. Murnighan,
K. Williams Phillips, and two anonymous referees for
their helpful comments. The Northwestern Institute on
Complex Systems provided financial support.
Supporting Online Material
www.sciencemag.org/cgi/content/full/1136099/DC1
SOM Text
Figs. S1 to S5
Tables S1 to S5
References
10 October 2006; accepted 3 April 2007
Published online 12 April 2007;
10.1126/science.1136099
Include this information when citing this pap er.
MET Amplification Leads to Gefitinib
Resistance in Lung Cancer by
Activating ERBB3 Signaling
Jeffrey A. Engelman,
1,2,3
Kreshnik Zejnullahu,
4,5
Tetsuya Mitsudomi,
6
Youngchul Song,
2,3
Courtney Hyland,
7
Joon Oh Park,
4,5
Neal Lindeman,
7
Christopher-Michael Gale,
3
Xiaojun Zhao,
5
James Christensen,
8
Takayuki Kosaka,
6
Alison J. Holmes,
4,5
Andrew M. Rogers,
5
Federico Cappuzzo,
9
Tony Mok,
10
Charles Lee,
7
Bruce E. Johnson,
4,5
Lewis C. Cantley,
2,3
Pasi A. Jänne
4,5
*
The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective
treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop
drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed
resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of
MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in
4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We
find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent
activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we
propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
T
yrosine kinase inhibitors (TKIs) are an
emerging class of anticancer therapies that
have shown promising clinical activity.
Gefitinib (Iressa) and erlotinib (T arcev a) inhibit
the epidermal growth factor receptor (EGFR) ki-
nase and are used to treat non–small cell lung
cancers (NSCLCs) that have activating mutations
in the EGFR gene (1–4). Although most EGFR
mutant NSCLCs initially respond to EGFR in-
hibitors, the vast majority of these tumors ulti-
mately become resistant to the drug treatment. In
about 50% of these cases, resistance is due to the
occurrence of a secondary mutation in EGFR
(T790M) (5, 6). The mechanisms that contribute
to resistance in the remaining tumors are
unknown.
To explore additional mechanisms of gefitinib
resistance, we generated resistant clones of the
gefitinib hypersensitive EGFR exon 19 mutant
NSCLC cell line, HCC827, by exposing these
cells to increasing concentrations of gefitinib for
6 months. The resultant cell line, HCC827 GR
(gefitinib resistant), and six clones isolated from
single cells were resistant to gefitinib in vitro
(IC
50
>10mM) (Fig. 1A). Unlike in the parental
HCC827 cells, phosphorylation of ERBB3 and
Akt in the HCC827 GR cells was maintained in
the presence of gefitinib (Fig. 1B).
We previously observed that EGFR mutant
tumors activate phosphoinositide 3-kinase
(PI3K)/Akt signaling through ERBB3 and that
down-regulation of the ERBB3/PI3K/Akt signal-
ing pathway is required for gefitinib to induce
apoptosis in EGFR mutant cells (7, 8). In addi-
tion, persistent ERBB3 phosphorylation has also
been associated with gefitinib resistance in
ERBB2-amplified breast cancer cells (9). We
therefore hypothesized that gefitinib resistance in
EGFR mutant NSCLCs might involve sustained
signal ing via ERBB3. After excluding the
presence of a secondary resistance mutation in
EGFR (10), we investigated whether aberrant
activation of anoth er receptor might be mediating
the resistance. We used a phospho–receptor tyro-
sine kinase (phospho-RTK) array to compare the
effects of gefitinib on 42 phosphorylated RTKs in
HCC827 and HCC827 GR5 cells (Fig. 1C). In
the parental cell line, EGFR, ERBB3, ERBB2,
and MET were all phosphorylated, and this phos-
phorylation was either completely or markedly
reduced upon gefitinib treatment. In contrast,
in the resistant cells, phosphorylation of MET,
ERBB3, and EGFR persisted at higher levels in
the presence of gefitinib (Fig. 1C).
We next performed genome-wide copy num-
ber analyses and mRNA expression profiling of
the HCC827 GR cell lines and compared them
with the parental HCC827 cells (fig. S1 and table
S1). The resistant but not parental cell lines
showed a marked focal amplification within chro-
mosome 7q31.1 to 7q33.3, which contains the
MET proto-oncogene (Fig. 1D). MET encodes a
transmembrane tyrosine kinase receptor for the
hepatocyte growth factor (scatter factor), and MET
amplification has been detected in gastric and
esophageal cancers (11 , 12). Analysis by quanti-
tative polymerase chain reaction (PCR) confirmed
that MET wasamplifiedbyafactorof5to10in
the resistant cells (fig. S2), and sequence analysis
provided no evidence of mutations in MET .
To determine whether increased MET
signaling underlies the acquired resistance to
gefitinib, we examined whether MET inhibition
suppressed growth of the resistant cells. HCC827
GR cells were exposed to PHA-665752, a MET
tyrosine kinase inhibitor, alone or in combination
with gefitinib (13). Although the HCC827 GR5
cells were resistant to both gefitinib alone and
PHA-665752 alone, combined treatment resulted
1
Massachusetts General Hospital Cancer Center, Boston,
MA 02114, USA.
2
Department of Systems Biology, Harvard
Medical School, Boston, MA 02115, USA.
3
Department of
Signal Transduction, Beth Israel Deaconess Medical Center,
Boston, MA 02115, USA.
4
Lowe Center for Thoracic Oncolo-
gy, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
5
Department of Medical Oncology, Dana-Farber Cancer
Institute, Boston, MA 02115, USA.
6
Department of Thoracic
Surgery, Aichi Cancer Center Hospital, Nagoya 464-8681,
Japan.
7
Department of Pathology, Brigham and Women’s
Hospital, Boston, MA 02115, USA.
8
Pfizer Global Research
and Development, Department of Research Pharmacology, La
Jolla Laboratories, La Jolla, CA 92121, USA.
9
Istituto Clinico
Humanitas, Department on Hematology-Oncology, Rozzano
20089, Italy.
10
Department of Clinical Oncology, Chinese
University of Hong Kong, Shatin, New Territories, Hong
Kong, China.
*To whom correspondence should be addressed. E-mail:
pjanne@partners.org
www.sciencemag.org SCIENCE VOL 316 18 MAY 2007 1039
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