• Activating somatic mutations in MAPK pathway genes are enriched among CLL patients who did not respond to PI3K inhibitors.

  • Activation of pERK is observed in primary and acquired PI3K resistance regardless of mutational status.

Inhibitors of Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase δ (PI3Kδ) that target the B-cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Mutations associated with resistance to BTK inhibitors have been identified, but limited data are available on mechanisms of resistance to PI3Kδ inhibitors. Here we present findings from longitudinal whole-exome sequencing of cells from patients with multiply relapsed CLL (N = 28) enrolled in trials of PI3K inhibitors. The nonresponder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF, and KRAS genes in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in nonresponder CLL cells with and without mutations, whereas treatment with a MEK inhibitor rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδ inhibitors in CLL and provide a rationale for therapy with a combination of PI3Kδ and ERK inhibitors.

1.
Janku
F
,
Yap
TA
,
Meric-Bernstam
F
.
Targeting the PI3K pathway in cancer: are we making headway?
Nat Rev Clin Oncol
.
2018
;
15
(
5
):
273
-
291
.
2.
Fruman
DA
,
Chiu
H
,
Hopkins
BD
,
Bagrodia
S
,
Cantley
LC
,
Abraham
RT
.
The PI3K pathway in human disease
.
Cell
.
2017
;
170
(
4
):
605
-
635
.
3.
Dong
S
,
Harrington
BK
,
Hu
EY
, et al
.
PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression
.
J Clin Invest
.
2019
;
129
(
1
):
122
-
136
.
4.
Hoellenriegel
J
,
Meadows
SA
,
Sivina
M
, et al
.
The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia
.
Blood
.
2011
;
118
(
13
):
3603
-
3612
.
5.
Brown
JR
,
Byrd
JC
,
Coutre
SE
, et al
.
Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia
.
Blood
.
2014
;
123
(
22
):
3390
-
3397
.
6.
Brown
JR
.
The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia
.
Semin Oncol
.
2016
;
43
(
2
):
260
-
264
.
7.
Raedler
LA
.
Zydelig (idelalisib): First-in-class PI3 kinase inhibitor approved for the treatment of 3 hematologic malignancies
.
Am Health Drug Benefits
.
2015
;
8
(
spec feature
):
157
-
162
.
8.
Eldfors
S
,
Kuusanmäki
H
,
Kontro
M
, et al
.
Idelalisib sensitivity and mechanisms of disease progression in relapsed TCF3-PBX1 acute lymphoblastic leukemia
.
Leukemia
.
2017
;
31
(
1
):
51
-
57
.
9.
Iyengar
S
,
Clear
A
,
Bödör
C
, et al
.
P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse
.
Blood
.
2013
;
121
(
12
):
2274
-
2284
.
10.
Serra
V
,
Scaltriti
M
,
Prudkin
L
, et al
.
PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer
.
Oncogene
.
2011
;
30
(
22
):
2547
-
2557
.
11.
Shukla
A
,
Shukla
V
,
Joshi
SS
.
Regulation of MAPK signaling and implications in chronic lymphocytic leukemia
.
Leuk Lymphoma
.
2018
;
59
(
7
):
1565
-
1573
.
12.
Landau
DA
,
Tausch
E
,
Taylor-Weiner
AN
, et al
.
Mutations driving CLL and their evolution in progression and relapse
.
Nature
.
2015
;
526
(
7574
):
525
-
530
.
13.
Cibulskis
K
,
Lawrence
MS
,
Carter
SL
, et al
.
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples
.
Nat Biotechnol
.
2013
;
31
(
3
):
213
-
219
.
14.
Lawrence
MS
,
Stojanov
P
,
Mermel
CH
, et al
.
Discovery and saturation analysis of cancer genes across 21 tumour types
.
Nature
.
2014
;
505
(
7484
):
495
-
501
.
15.
Robinson
JT
,
Thorvaldsdóttir
H
,
Winckler
W
, et al
.
Integrative genomics viewer
.
Nat Biotechnol
.
2011
;
29
(
1
):
24
-
26
.
16.
Carter
SL
,
Cibulskis
K
,
Helman
E
, et al
.
Absolute quantification of somatic DNA alterations in human cancer
.
Nat Biotechnol
.
2012
;
30
(
5
):
413
-
421
.
17.
Kasar
S
,
Kim
J
,
Improgo
R
, et al
.
Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
.
Nat Commun
.
2015
;
6
(
1
):
8866
.
18.
Leshchiner
I
,
Livitz
D
,
Gainor
JF
, et al
.
Comprehensive analysis of tumour initiation, spatial and temporal progression under multiple lines of treatment
.
bioRxiv
. Posted 31 December 2018.
19.
Liberzon
A
,
Subramanian
A
,
Pinchback
R
,
Thorvaldsdóttir
H
,
Tamayo
P
,
Mesirov
JP
.
Molecular signatures database (MSigDB) 3.0
.
Bioinformatics
.
2011
;
27
(
12
):
1739
-
1740
.
20.
Landau
DA
,
Carter
SL
,
Stojanov
P
, et al
.
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia
.
Cell
.
2013
;
152
(
4
):
714
-
726
.
21.
Wang
L
,
Lawrence
MS
,
Wan
Y
, et al
.
SF3B1 and other novel cancer genes in chronic lymphocytic leukemia
.
N Engl J Med
.
2011
;
365
(
26
):
2497
-
2506
.
22.
Puente
XS
,
Beà
S
,
Valdés-Mas
R
, et al
.
Non-coding recurrent mutations in chronic lymphocytic leukaemia
.
Nature
.
2015
;
526
(
7574
):
519
-
524
.
23.
Emery
CM
,
Monaco
KA
,
Wang
P
, et al
.
BRAF-inhibitor associated MEK mutations increase RAF-dependent and -independent enzymatic activity
.
Mol Cancer Res
.
2017
;
15
(
10
):
1431
-
1444
.
24.
Emery
CM
,
Vijayendran
KG
,
Zipser
MC
, et al
.
MEK1 mutations confer resistance to MEK and B-RAF inhibition
.
Proc Natl Acad Sci USA
.
2009
;
106
(
48
):
20411
-
20416
.
25.
Arcila
ME
,
Drilon
A
,
Sylvester
BE
, et al
.
MAP2K1 (MEK1) mutations define a distinct subset of lung adenocarcinoma associated with smoking
.
Clin Cancer Res
.
2015
;
21
(
8
):
1935
-
1943
.
26.
Gao
Y
,
Chang
MT
,
McKay
D
, et al
.
Allele-specific mechanisms of activation of MEK1 mutants determine their properties
.
Cancer Discov
.
2018
;
8
(
5
):
648
-
661
.
27.
Frémin
C
,
Meloche
S
.
From basic research to clinical development of MEK1/2 inhibitors for cancer therapy
.
J Hematol Oncol
.
2010
;
3
(
1
):
8
.
28.
Moschos
SJ
,
Sullivan
RJ
,
Hwu
WJ
, et al
.
Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors
.
JCI Insight
.
2018
;
3
(
4
):
e92352
.
29.
Wagle
N
,
Van Allen
EM
,
Treacy
DJ
, et al
.
MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition
.
Cancer Discov
.
2014
;
4
(
1
):
61
-
68
.
30.
Zwang
Y
,
Jonas
O
,
Chen
C
, et al
.
Synergistic interactions with PI3K inhibition that induce apoptosis
.
eLife
.
2017
;
6
:
e24523
.
31.
Cheng
S
,
Guo
A
,
Lu
P
,
Ma
J
,
Coleman
M
,
Wang
YL
.
Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors
.
Leukemia
.
2015
;
29
(
4
):
895
-
900
.
32.
Chen
JG
,
Liu
X
,
Munshi
M
, et al
.
BTKCys481Ser drives ibrutinib resistance via ERK1/2 and protects BTKwild-type MYD88-mutated cells by a paracrine mechanism
.
Blood
.
2018
;
131
(
18
):
2047
-
2059
.
33.
Scheffold
A
,
Jebaraj
BMC
,
Bloehdorn
J
, et al.
High IGF1R expression is associated with worse prognosis in CLL and impacts response to PI3K-δ inhibitor treatment [abstract]
.
Blood
.
2017
;
130
(
suppl 1
). Abstract 390.
34.
Scheffold
A
,
Jebaraj
BMC
,
Tausch
E
, et al
.
IGF1R as druggable target mediating PI3K-δ inhibitor resistance in a murine model of chronic lymphocytic leukemia
.
Blood
.
2019
;
134
(
6
):
534
-
547
.
35.
Wen
BG
,
Pletcher
MT
,
Warashina
M
, et al
.
Inositol (1,4,5) trisphosphate 3 kinase B controls positive selection of T cells and modulates Erk activity
.
Proc Natl Acad Sci USA
.
2004
;
101
(
15
):
5604
-
5609
.
36.
Elich
M
,
Sauer
K
.
Regulation of hematopoietic cell development and function through phosphoinositides
.
Front Immunol
.
2018
;
9
:
931
.
37.
Cheng
Y
,
Tian
H
.
Current development status of MEK inhibitors
.
Molecules
.
2017
;
22
(
10
):
1551
.
38.
Liu
F
,
Yang
X
,
Geng
M
,
Huang
M
.
Targeting ERK, an Achilles’ heel of the MAPK pathway, in cancer therapy
.
Acta Pharm Sin B
.
2018
;
8
(
4
):
552
-
562
.
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