bluuebunny/crossref_metadata_2025 huggingface dataset:
First operation of an ALICE OROC operated in high pressure $${\text {Ar-CO}}_2$$ and $$\text {Ar-CH}_4$$
Authors: Ritchie-Yates A. , Deisting A. , Barker G. , Boyd S. , Brailsford D. , Chen-Wishart Z. , Cremonesi L. , Dunne P. , Eeles J. , Hamilton P. , Kaboth A. C. , Khan N. , Klustová A. , Monroe J. , Nowak J. , Singh P. , Waldron A. V. , Walding J. , Warsame L. , Wascko M. O. , Xiotidis I.
Published: December 2023

New neutrino–nucleus interaction cross-section measurements are required to improve nuclear models sufficiently for future long baseline neutrino experiments to meet their sensitivity goals. A time projection chamber (TPC) filled with a high-pressure gas is a promising detector to characterise the neutrino sources used for such experiments. A gas-filled TPC is ideal for measuring low-energy particles, which travel further in gas than in solid or liquid detectors and using high-pressure increases the target density, resulting in more neutrino interactions. We examine the suitability of multiwire proportional chambers (MWPCs) from the ALICE TPC for use as the readout chambers of a high-pressure gas TPC. These chambers were previously operated at atmospheric pressure. We report the successful operation of an ALICE TPC outer readout chamber (OROC) at pressures up to 4.2 bar absolute (barA) with $$\text {Ar-CH}_4$$

Ar-CH
4

mixtures with a $$\text {CH}_{4}$$

CH
4

content between 2.8 and 5.0%, and so far up to 4 bar absolute with $${\text {Ar-CO}}_2$$

Ar-CO
2

(90-10). The charge gain of the OROC was measured with signals induced by an $$^{55}\text {Fe}$$

55

Fe

source. The largest gain achieved at 4.2 bar was $$(29\pm 1)\cdot 10^{3}$$

(
29
±
1
)

·

10
3

in $$\text {Ar-CH}_4$$

Ar-CH
4

with 4.0% $$\text {CH}_{4}$$

CH
4

with an anode voltage of $${2975}\,\hbox {V}$$

2975

V

. In $${\text {Ar-CO}}_2$$

Ar-CO
2

with 10% $$\text {CO}_{2}$$

CO
2

at 4 barA, a gain of $$(4.2\pm 0.1)\cdot 10^{3}$$

(
4.2
±
0.1
)

·

10
3

was observed with anode voltage $${2975}\,\hbox {V}$$

2975

V

. We extrapolate that at 10 barA, an interesting pressure for future neutrino experiments, a gain of 5000 in $${\text {Ar-CO}}_2$$

Ar-CO
2

with 10% $$\text {CO}_{2}$$

CO
2

(10,000 in $$\text {Ar-CH}_4$$

Ar-CH
4

with $$\sim \!{4}{\%}$$

∼

4
%

$$\text {CH}_{4}$$

CH
4

) may be achieved with anode voltage of $${4.6}\,\hbox {kV}$$

4.6

kV

($$\sim \!{3.6}\,\hbox {kV}$$

∼

3.6

kV

).
Using entropy bounds to avoid the cosmological singularity and constrain cosmological particle production
Authors: Yu Hao , Li Jin
Published: December 2023

In this work, we study the applications of entropy bounds in two toy cosmological models with particle production (annihilation), i.e., a radiation-dominated universe and a dust-dominated universe. We consider the co-moving volume and the volume covered by the particle horizon of a given observer as the thermodynamic systems satisfying entropy bounds. For the Bekenstein bound and the spherical entropy bound, it is found that the cosmological singularity can be avoided and cosmological particle production needs to be truncated in some special cases. Our study can be extended to other cosmological models with particle production.
Scalarized black holes in new massive gravity dressed by a nonminimally coupled scalar
Authors: Myung Yun Soo
Published: December 2023

We investigate scalarized black holes in new massive gravity dressed by a nonminimally coupled scalar. For this purpose, we find the Gregory–Laflamme (GL) and tachyonic instability bounds of bald BTZ black hole expressed in terms of $$m^2$$

m
2

a massive spin-2 parameter and $$\alpha $$
α
a scalar coupling parameter to Ricci scalar by making use of the linearized theory around black hole. On the other hand, we obtain a solution bound of $$0.161<\alpha <3/16$$

0.161
<
α
<
3
/
16

for achieving non-BTZ black holes with scalar hair analytically and a thermodynamic bound of $$1/8<\alpha <13/80$$

1
/
8
<
α
<
13
/
80

for obtaining consistent thermodynamic quantities. Without imposing the GL instability bound $$(m^2<1/2\ell ^2),$$

(

m
2

<
1
/
2

ℓ
2

)
,

we find a very narrow bound of $$0.161<\alpha <0.1625$$

0.161
<
α
<
0.1625

which is located inside tachyonic instability bound of $$\alpha >1/8+m^2_{\Phi } \ell ^2/6$$

α
>
1
/
8
+

m
Φ
2

ℓ
2

/
6

for obtaining scalarized black holes where $$m^2_{\Phi }$$

m
Φ
2

is a scalar mass parameter.
THE TWO-SCALE FRACTAL DIMENSION: A UNIFYING PERSPECTIVE TO METABOLIC LAW
Authors: AIN QURA TUL , HE JI-HUAN , QIANG XIAO-LI , KOU ZHENG
Published: December 2023

The laws governing life should be as simple as possible; however, theoretical investigations into allometric laws have become increasingly complex, with the long-standing debate over the scaling exponent in allometric laws persisting. This paper re-examines the same biological phenomenon using two different scales. On a macroscopic scale, a cell surface appears smooth, but on a smaller scale, it exhibits a fractal-like porous structure. To elaborate, a few examples are given. Employing the two-scale fractal theory, we theoretically predict and experimentally verify the scaling exponent values for basal, active, and maximal metabolic rates. This paper concludes that Rubner’s 2/3 law and Kleiber’s 3/4 law are two facets of the same truth, manifested across different scale approximations.
Bridges and Mechanisms: Integrating Systems Science Thinking into Implementation Research
Authors: Luke Douglas A. , Powell Byron J. , Paniagua-Avila Alejandra
Published: December 2023

We present a detailed argument for how to integrate, or bridge, systems science thinking and methods with implementation science. We start by showing how fundamental systems science principles of structure, dynamics, information, and utility are relevant for implementation science. Then we examine the need for implementation science to develop and apply richer theories of complex systems. This can be accomplished by emphasizing a causal mechanisms approach. Identifying causal mechanisms focuses on the “cogs and gears” of public health, clinical, and organizational interventions. A mechanisms approach focuses on how a specific strategy will produce the implementation outcome. We show how connecting systems science to implementation science opens new opportunities for examining and addressing social determinants of health and conducting equitable and ethical implementation research. Finally, we present case studies illustrating successful applications of systems science within implementation science in community health policy, tobacco control, health care access, and breast cancer screening.
Electrocatalytic Amplified Sensor For Determination of Ofloxacin Using Zn2SnO4/Reduced Graphene Oxide Composite As Surface-Modifying Agent
Authors: de Castro Janevane S. , Chaves Anderson V. , Fechine Pierre B. A. , de Oliveira Raíssa C. , Ribeiro Francisco W. P. , de Lima-Neto Pedro , Abreu Dieric S. , de Oliveira Cristiani L. C. G. , Correia Adriana N.
Published: December 2023

This study describes an electroanalytical approach for the quantification of ofloxacin (OFL) through an electrochemical sensor based on a glassy carbon electrode modified with composite material (Zn2SnO4-rGO/GCE) using square wave voltammetry. Zn2SnO4 was synthesized by hydrothermal treatment and characterized by X-ray diffraction, Fourier-transform infrared and Raman spectroscopy and scanning electron microscopy. The analysis suggests a synergistic effect between the composite material, indicating irreversible oxidation of OFL in its protonated form (OFL+), involving two electrons. The electroanalytical methodology was successfully applied to determine OFL in ophthalmic solutions samples, achieving recovery rates ranging from 98.03% to 104.91%. Furthermore, it demonstrated high stability in both repeatability (RSD = 3.20%, n = 12) and reproducibility (RSD = 4.64%, n = 7), with no observed interference when additional substances were added. These results suggest the potential electroanalytical application of Zn2SnO4 and recommend the developed methodology as an alternative tool for OFL determination in commercial pharmaceutical samples.
From the President: ECS Toward Sustainability
Authors: Botte Gerardine G.
Published: December 2023

dear ECS friends, I write to you following two incredible gatherings of the global ECS community. The first was the 244th ECS meeting in Gothenburg, Sweden. There we assembled, over 3,400 strong—the largest meeting ECS has held outside of PRiME—to enrich and energize our professional lives and celebrate our triumphant return to hosting meetings in Europe. The second was the annual meetings of the Sociedad Mexicana de Electroquímica (SMEQ) and ECS Mexico Section.
Websites of Note - Winter 2023
Authors: Suroviec Alice H.
Published: December 2023

Websites of Note Selected for You by Alice H. Suroviec
Comparison of Barrier Efficiency for Self-Assembled Monolayers on SiO2 by Using Decyltrimethoxysilane or 3-Aminopropyltrimethoxysilane Vapor Treatment
Authors: Cheng Yi-Lung , Lee Chih-Yen , Chen Giin-Shan , Fang Jau-Shiung
Published: December 2023

Self-assembled monolayers (SAMs) are the emerging materials as the candidate of barriers used in back-end-of–line interconnects for future generation. In this study, SAMs were formed on the SiO2 film by using decyltrimethoxysilane (DTMOS) or 3-aminopropyltrimethoxysilane (APTMS) in the vapor phase at a temperature of 100 °C. Barrier efficiency of the formation SAMS at the surface of SiO2 films under thermal and electrical stress was investigated from the perspective of the electrical characteristics. The formation of SAMs onto the SiO2 films by DTMOS and APTMS vapor treatment enhanced the adhesion, dielectric breakdown field and barrier against Cu migration under thermal stress. Additionally, APTMS-SAMs had a larger improvement. Under electrical stress with field larger than 6.5 MV cm−1, DTMOS-SAMs lost barrier effectiveness due to weak bonding structure. APTMS-SAMs still had the barrier capacity.
The Role of Alanine in the Chemical Mechanical Polishing of Aluminum
Authors: Cao Yuwei , Wang Shengli , Luo Chong , Wang Chenwei , Qi Yuhang , Yan Xianwen , Wang Qiang , Yang Yundian
Published: December 2023

With the evolution of integrated circuits, the transition from polycrystalline silicon to aluminum as the gate electrode has become prevalent due to its inherent advantages. This study considers the impacts of pH, H2O2 and alanine on the aluminum removal rate and surface roughness during chemical mechanical polishing (CMP) with abrasive colloidal silica. Alanine was incorporated as a complexing agent in the polishing slurry in an acidic environment. The mechanistic role of alanine in the aluminum CMP process was investigated with various techniques, including electrochemical tests, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and UV–visible spectroscopy (UV–vis). Additionally, density functional theory (DFT) calculations were used to examine the quantum chemical parameters of alanine and elucidate the complexation mechanism. The experimental results indicated that at an alanine concentration of 1.5 wt%, the Al removal rate was 2124.07 Å min−1 with a surface roughness of 1.33 nm. The interactions between alanine and the aluminum ions (Al3+) yielded soluble Al-alanine complexes, which facilitated corrosion on the Al and enhanced the removal rate.
Novel Surface-Enriched Spiky Ball With Spines NiCo2S4@GO/CNT Electrode Material for a High-Performance Flexible Asymmetric Supercapacitor
Authors: Ravisankar D. , Geetha D. , Ramesh P. S. , Vinothkumar V.
Published: December 2023

Nickel cobalt sulfide (NiCo2S4) nanoparticles on graphene oxide GO sheets and carbon nanotube (CNT) were fabricated successfully via a simple solvothermal route. Most NiCo2S4 nanoparticles cover both sides of the GO sheets, and the carbon nanotubes are arranged at the edge of the composite, creating a Spiky ball structure that effectively prevents the accumulation of GO. Synthesized hybrid nanocomposite (NiCo2S4/GO/CNT) has an optimum specific surface area and pore nature, and the coupling between CNT and GO enhances the electrochemical properties of NiCo2S4. The structural, morphological, and spectral characteristics were analysed using diffraction, microscopy, and spectroscopy techniques. To determine the electrochemical activity, cyclic voltammetry (CV), galvanostatic charge-discharge spectroscopy, and electrochemical impedance spectroscopy (EIS) were performed in a 3 M KOH electrolyte solution, the prepared sample was evaluated as an active electrode material for the supercapacitor. It delivers a very high specific capacitance of 845 Fg−1 at a current density of 2 Ag −1 as compared with NiCo2S4 (423 Fg−1). Coin cell was fabricated and tested using NiCo2S4/GO/CNT as cathode and graphite as an anode. The device exhibited an excellent energy density of 30.8 Wh kg−1, a power density of 3691 Wkg−1, and good cyclic stability with 82% retention after 1000 cycles.
Exploring the Privacy Paradox in Social Network Users: A Double-Entry Mental Accounting Theory Perspective
Authors: Pan Yuchen , Chen Huiping
Published: December 2023

Social networking service (SNS) users often express great concern for their personal privacy, yet continue to disclose personal information on these platforms. This privacy paradox between privacy concerns and disclosure behavior has drawn widespread academic attention. In this study, we use the double-entry mental accounting theory to construct a theoretical model and conduct an in-depth analysis of the privacy paradox phenomenon and its causes through empirical verification. Our research shows a significant positive correlation between perceived benefits and users’ intention to disclose privacy, while perceived risks and users’ intention to disclose privacy are significantly negatively correlated. The double-entry mental accounting theory plays a crucial role in mediating the relationship between perceived values and users’ intention to disclose privacy. Furthermore, we found that information sensitivity negatively regulates the relationship between perceived risks, the pleasure attenuation coefficient α, the pain buffering coefficient β, and the intention to disclose privacy. Our study provides theoretical and empirical information on the reasons for the privacy paradox and offers insights for social networking service providers to optimize their services.
Strategies for the High Average zT in the Electron-Doped SnTe
Authors: Park Hyunjin , Lee Kyu Hyoung , Heo Minsu , Kim Sang-il , Kim Hyun-Sik
Published: December 2023

We propose a new strategy to achieve a high average zT in electron-doped SnTe by applying the two-band (TB) and single parabolic band (SPB) models to the electronic transport properties of Sn0.97M0.03Te (

M
=
Ga

, In, Bi, and Sb) reported in the literature. To achieve a high average zT at temperatures from 300 to 823 K, both zT at 300 and 823 K should be high with a steadily increasing zT over the temperatures. The p-type SnTe is known to have a light valence band and a heavy valence band that are approximately 0.40 eV apart. The Bi-doped SnTe exhibits one of the highest zT among all the other doped samples at 300 K (0.09) and the highest zT at 823 K (0.9), with a steadily increasing zT in between. The TB model confirms the presence of the resonant state at 300 K which is responsible for the high zT at 300 K. The B-factor, which is related to the theoretical maximum zT, calculated by the SPB model indicates a steady increase in zT with increasing temperature. The temperature-dependent B-factor of the Bi-doped SnTe suggests that the initial position of its Fermi level at 300 K calculated by the TB model may be responsible for the temperature coefficient of the B-factor, which determines the zT at 823 K. According to the SPB model, experimental zT of 0.9 of the Bi-doped SnTe can be further improved to 1.03 (14% improvement) at 823 K upon carrier concentration optimization. To achieve a high average zT in SnTe, electron doping with a dopant that forms a resonant state and placing the Fermi level at the light valence band in the vicinity of the heavy valence band maximum are both essential.
Vortex-Induced Force Identification of a Long-Span Bridge Based on Field Measurement Data
Authors: Jiang S. J. , Xu Y. L. , Zhu J. , Zhang G. Q. , Dan D. H.
Published: December 2023

Vortex-induced force (VIF) identification and modelling of a long-span bridge are often conducted in terms of aeroelastic sectional model tests in wind tunnels. However, there are uncertainties inherent in wind tunnel model tests so that vortex-induced vibration (VIV) still occurs in real long-span bridges designed according to wind tunnel test results. This paper presents a framework for VIF identification of a long-span bridge based on field-measured wind and acceleration data. The framework is composed of the four steps: (1) decompose field-measured acceleration response time histories using variational mode decomposition (VMD) method; (2) obtain velocity and displacement response time histories using frequency domain integration (FDI) method; (3) establish and update the finite element model and identify the generalized VIF time histories of the bridge; and (4) identify the parameters in the polynomial VIF models and decide the most suitable VIF model. The proposed framework is finally applied to a real suspension bridge with a recent VIV event. The results show that the proposed framework can accurately identify the generalized VIF acting on the bridge from the field-measured acceleration and wind data, and the derived most suitable VIF model can produce almost the same vortex-induced response (VIR) as the measured ones.
ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4
Authors: Yang Liu , Jing Yue , Xia Xia , Yin Xiushan
Published: December 2023

Objective. The bromodomain-containing 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family, which is an important epigenetic reader. It is currently a promising oncology target. In some tumors, BET bromodomain inhibitors have demonstrated promising results. Proteolysis-targeting methods (PROTAC), which rapidly and effectively degrade BRD4, have displayed considerable potential in the treatment of tumors in recent years. The purpose of this study is to examine the potential impact of BRD4 PROTAC compounds ARV-825 on oncogene BRD4-NUT fused protein in NUT carcinoma. Methods. The effectiveness of ARV-825 was evaluated at the cellular level using the cell counting kit 8 test, wound healing, cell transfection, western blotting analysis, and RNA sequencing. The effectiveness of ARV-825 was also examined in vivo using a xenograft model. Results. The BRD4-NUT fusion gene was overexpressed in 3T3 cells, and the pathogenic fusion gene was simulated. The results showed that the overexpression of BRD4-NUT could promote the proliferation and migration of 3T3 cells, but the expression of BRD4 protein was degraded after the addition of the novel cereblon-based PROTAC compound ARV-825 against BRD4, resulting in inhibition of BRD4-NUT 3T3 cell proliferation and migration. Further RNA-seq analysis showed that overexpression of BRD4-NUT was accompanied by increased expression of gene (e.g., Myc, E2F, TRAFs, Wnt, Gadd45g, and Sox6) with significantly enriched pathway (e.g., small cell lung cancer, NF-kappa B signaling pathway, and breast cancer), promoted cell cycle from G 1 phase to S phase, and increased cell proliferation and migration, activated the antiapoptosisi signal, led to abnormal cell growth, and ultimately led to tumorigenesis. The addition of ARV-825 effectively rescued this process and effectively inhibited cell vitality, proliferation, and migration. In vivo studies demonstrated that treatment with ARV-825 greatly suppressed tumor growth without causing harmful side effects and downregulated the BRD4-NUT expression level. Conclusion. Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event.
Supplementary Figure 3 from RETRACTED: Physical and Functional Interaction of DNA Methyltransferase 3A with Mbd3 and Brg1 in Mouse Lymphosarcoma Cells
Authors: Datta Jhrana , Majumder Sarmila , Bai Shoumei , Ghoshal Kalpana , Kutay Huban , Smith David Spencer , Crabb John W. , Jacob Samson T.
Published: December 2023

Supplementary Figure 3 from RETRACTED: Physical and Functional Interaction of DNA Methyltransferase 3A with Mbd3 and Brg1 in Mouse Lymphosarcoma Cells
Table S3. CBC+CMP from LILRB3 CAR T adoptively transferred LILRB3 transgenic mice from LILRB3 Modulates Acute Myeloid Leukemia Progression and Acts as an Effective Target for CAR T-cell Therapy
Authors: Mai Sunny , Hodges Alan , Chen Hui-Ming , Zhang Jilu , Wang Yi-Ling , Liu Yongbin , Nakatsu Fumiko , Wang Xiaoxuan , Fang Jing , Xu Yitian , Davidov Vitaliy , Kang Kyeongah , Pingali Sai Ravi , Ganguly Siddhartha , Suzuki Masataka , Konopleva Marina , Prinzing Brooke , Zu Youli , Gottschalk Stephen , Lu Yong , Chen Shu-Hsia , Pan Ping-Ying
Published: December 2023

Complete Blood Counts and Metabolic Panel for LILRB3 specific CAR adoptively transferred LILRB3 transgenic naive mice.
Supplementary Figures from LILRB3 Modulates Acute Myeloid Leukemia Progression and Acts as an Effective Target for CAR T-cell Therapy
Authors: Mai Sunny , Hodges Alan , Chen Hui-Ming , Zhang Jilu , Wang Yi-Ling , Liu Yongbin , Nakatsu Fumiko , Wang Xiaoxuan , Fang Jing , Xu Yitian , Davidov Vitaliy , Kang Kyeongah , Pingali Sai Ravi , Ganguly Siddhartha , Suzuki Masataka , Konopleva Marina , Prinzing Brooke , Zu Youli , Gottschalk Stephen , Lu Yong , Chen Shu-Hsia , Pan Ping-Ying
Published: December 2023

S. Figs. 1-9
Supplementary Figures from Super Enhancer–Regulated LncRNA LINC01089 Induces Alternative Splicing of DIAPH3 to Drive Hepatocellular Carcinoma Metastasis
Authors: Su Tao , Zhang Nasha , Wang Teng , Zeng Jiajia , Li Wenwen , Han Linyu , Yang Ming
Published: December 2023

Supplementary Figure 1-8
Supplementary Tables from FGFR3 Alterations in Bladder Cancer Stimulate Serine Synthesis to Induce Immune-Inert Macrophages That Suppress T-cell Recruitment and Activation
Authors: Ouyang Yi , Ou Ziwei , Zhong Wenlong , Yang Jin , Fu Sha , Ouyang Nengtai , Chen Junyu , Xu Longhao , Wu Daqin , Qian Junan , Lin Yi , Lin Tianxin , Huang Jian
Published: December 2023

Supplementary Table 1-4
Table S6 from TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
Authors: Edwards A. Cole , Stalnecker Clint A. , Jean Morales Alexis , Taylor Khalilah E. , Klomp Jennifer E. , Klomp Jeffrey A. , Waters Andrew M. , Sudhakar Niranjan , Hallin Jill , Tang Tracy T. , Olson Peter , Post Leonard , Christensen James G. , Cox Adrienne D. , Der Channing J.
Published: December 2023

Plasmids utilized in this study
Figure s.4 from Fructose-Induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy
Authors: Cui Yanfen , Tian Jianfei , Wang Zhaosong , Guo Hui , Zhang He , Wang Zhiyong , Liu Hui , Song Weijie , Liu Liming , Tian Ruinan , Zuo Xiaoyan , Ren Sixin , Niu Ruifang , Zhang Fei
Published: December 2023

Figure s4
Figure S5 from Fructose-Induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy
Authors: Cui Yanfen , Tian Jianfei , Wang Zhaosong , Guo Hui , Zhang He , Wang Zhiyong , Liu Hui , Song Weijie , Liu Liming , Tian Ruinan , Zuo Xiaoyan , Ren Sixin , Niu Ruifang , Zhang Fei
Published: December 2023

Figure S5
Figure S4 from TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
Authors: Edwards A. Cole , Stalnecker Clint A. , Jean Morales Alexis , Taylor Khalilah E. , Klomp Jennifer E. , Klomp Jeffrey A. , Waters Andrew M. , Sudhakar Niranjan , Hallin Jill , Tang Tracy T. , Olson Peter , Post Leonard , Christensen James G. , Cox Adrienne D. , Der Channing J.
Published: December 2023

Supplementary Figure 4
Figure S3 from TEAD Inhibition Overcomes YAP1/TAZ-Driven Primary and Acquired Resistance to KRASG12C Inhibitors
Authors: Edwards A. Cole , Stalnecker Clint A. , Jean Morales Alexis , Taylor Khalilah E. , Klomp Jennifer E. , Klomp Jeffrey A. , Waters Andrew M. , Sudhakar Niranjan , Hallin Jill , Tang Tracy T. , Olson Peter , Post Leonard , Christensen James G. , Cox Adrienne D. , Der Channing J.
Published: December 2023

Supplementary Figure 3
Supplementary Figures and Tables from Topoisomerase 1 Inhibition in MYC-Driven Cancer Promotes Aberrant R-Loop Accumulation to Induce Synthetic Lethality
Authors: Lin Peter , Lourenco Corey , Cruickshank Jennifer , Palomero Luis , van Leeuwen Jenna E. , Tong Amy H. Y. , Chan Katherine , El Ghamrasni Samah , Pujana Miquel Angel , Cescon David W. , Moffat Jason , Penn Linda Z.
Published: December 2023

Includes Supplemental Figures S1-S6 and Supplemental Tables S1-S6.
Table S5 from Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma
Authors: Wu Yige , Chen Siqi , Yang Xiaolu , Sato Kazuhito , Lal Preet , Wang Yuefan , Shinkle Andrew T. , Wendl Michael C. , Primeau Tina M. , Zhao Yanyan , Gould Alanna , Sun Hua , Mudd Jacqueline L. , Hoog Jeremy , Mashl R. Jay , Wyczalkowski Matthew A. , Mo Chia-Kuei , Liu Ruiyang , Herndon John M. , Davies Sherri R. , Liu Di , Ding Xi , Evrard Yvonne A. , Welm Bryan E. , Lum David , Koh Mei Yee , Welm Alana L. , Chuang Jeffrey H. , Moscow Jeffrey A. , Meric-Bernstam Funda , Govindan Ramaswamy , Li Shunqiang , Hsieh James , Fields Ryan C. , Lim Kian-Huat , Ma Cynthia X. , Zhang Hui , Ding Li , Chen Feng
Published: December 2023

Tumor volumes after 1-month and 2-month treatments
Table S4 from Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma
Authors: Wu Yige , Chen Siqi , Yang Xiaolu , Sato Kazuhito , Lal Preet , Wang Yuefan , Shinkle Andrew T. , Wendl Michael C. , Primeau Tina M. , Zhao Yanyan , Gould Alanna , Sun Hua , Mudd Jacqueline L. , Hoog Jeremy , Mashl R. Jay , Wyczalkowski Matthew A. , Mo Chia-Kuei , Liu Ruiyang , Herndon John M. , Davies Sherri R. , Liu Di , Ding Xi , Evrard Yvonne A. , Welm Bryan E. , Lum David , Koh Mei Yee , Welm Alana L. , Chuang Jeffrey H. , Moscow Jeffrey A. , Meric-Bernstam Funda , Govindan Ramaswamy , Li Shunqiang , Hsieh James , Fields Ryan C. , Lim Kian-Huat , Ma Cynthia X. , Zhang Hui , Ding Li , Chen Feng
Published: December 2023

Statistical tests for tumor volume changes
Supplementary Figure 6 from Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase
Authors: Rawat Chitra , Ben-Salem Salma , Singh Nidhi , Chauhan Gaurav , Rabljenovic Anja , Vaghela Vishwa , Venkadakrishnan Varadha Balaji , Macdonald Jonathan D. , Dahiya Ujjwal R. , Ghanem Yara , Bachour Salam , Su Yixue , DePriest Adam D. , Lee Sanghee , Muldong Michelle , Kim Hyun-Tae , Kumari Sangeeta , Valenzuela Malyn May , Zhang Dingxiao , Hu Qiang , Cortes Gomez Eduardo , Dehm Scott M. , Zoubeidi Amina , Jamieson Christina A.M. , Nicolas Marlo , McKenney Jesse , Willard Belinda , Klein Eric A. , Magi-Galluzzi Cristina , Stauffer Shaun R. , Liu Song , Heemers Hannelore V.
Published: December 2023

Supplementary Figure 6
Table S3 from Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma
Authors: Wu Yige , Chen Siqi , Yang Xiaolu , Sato Kazuhito , Lal Preet , Wang Yuefan , Shinkle Andrew T. , Wendl Michael C. , Primeau Tina M. , Zhao Yanyan , Gould Alanna , Sun Hua , Mudd Jacqueline L. , Hoog Jeremy , Mashl R. Jay , Wyczalkowski Matthew A. , Mo Chia-Kuei , Liu Ruiyang , Herndon John M. , Davies Sherri R. , Liu Di , Ding Xi , Evrard Yvonne A. , Welm Bryan E. , Lum David , Koh Mei Yee , Welm Alana L. , Chuang Jeffrey H. , Moscow Jeffrey A. , Meric-Bernstam Funda , Govindan Ramaswamy , Li Shunqiang , Hsieh James , Fields Ryan C. , Lim Kian-Huat , Ma Cynthia X. , Zhang Hui , Ding Li , Chen Feng
Published: December 2023

Treatments received by the patients
Supplementary Figure 5 from Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase
Authors: Rawat Chitra , Ben-Salem Salma , Singh Nidhi , Chauhan Gaurav , Rabljenovic Anja , Vaghela Vishwa , Venkadakrishnan Varadha Balaji , Macdonald Jonathan D. , Dahiya Ujjwal R. , Ghanem Yara , Bachour Salam , Su Yixue , DePriest Adam D. , Lee Sanghee , Muldong Michelle , Kim Hyun-Tae , Kumari Sangeeta , Valenzuela Malyn May , Zhang Dingxiao , Hu Qiang , Cortes Gomez Eduardo , Dehm Scott M. , Zoubeidi Amina , Jamieson Christina A.M. , Nicolas Marlo , McKenney Jesse , Willard Belinda , Klein Eric A. , Magi-Galluzzi Cristina , Stauffer Shaun R. , Liu Song , Heemers Hannelore V.
Published: December 2023

Supplementary Figure 5
Supplementary Figures from Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma
Authors: Wu Yige , Chen Siqi , Yang Xiaolu , Sato Kazuhito , Lal Preet , Wang Yuefan , Shinkle Andrew T. , Wendl Michael C. , Primeau Tina M. , Zhao Yanyan , Gould Alanna , Sun Hua , Mudd Jacqueline L. , Hoog Jeremy , Mashl R. Jay , Wyczalkowski Matthew A. , Mo Chia-Kuei , Liu Ruiyang , Herndon John M. , Davies Sherri R. , Liu Di , Ding Xi , Evrard Yvonne A. , Welm Bryan E. , Lum David , Koh Mei Yee , Welm Alana L. , Chuang Jeffrey H. , Moscow Jeffrey A. , Meric-Bernstam Funda , Govindan Ramaswamy , Li Shunqiang , Hsieh James , Fields Ryan C. , Lim Kian-Huat , Ma Cynthia X. , Zhang Hui , Ding Li , Chen Feng
Published: December 2023

Supplementary Figure S1-5
Supplementary Figure 2 from Prostate Cancer Progression Relies on the Mitotic Kinase Citron Kinase
Authors: Rawat Chitra , Ben-Salem Salma , Singh Nidhi , Chauhan Gaurav , Rabljenovic Anja , Vaghela Vishwa , Venkadakrishnan Varadha Balaji , Macdonald Jonathan D. , Dahiya Ujjwal R. , Ghanem Yara , Bachour Salam , Su Yixue , DePriest Adam D. , Lee Sanghee , Muldong Michelle , Kim Hyun-Tae , Kumari Sangeeta , Valenzuela Malyn May , Zhang Dingxiao , Hu Qiang , Cortes Gomez Eduardo , Dehm Scott M. , Zoubeidi Amina , Jamieson Christina A.M. , Nicolas Marlo , McKenney Jesse , Willard Belinda , Klein Eric A. , Magi-Galluzzi Cristina , Stauffer Shaun R. , Liu Song , Heemers Hannelore V.
Published: December 2023

Supplementary Figure 2
Supplementary Data 1 from Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma
Authors: Wu Yige , Chen Siqi , Yang Xiaolu , Sato Kazuhito , Lal Preet , Wang Yuefan , Shinkle Andrew T. , Wendl Michael C. , Primeau Tina M. , Zhao Yanyan , Gould Alanna , Sun Hua , Mudd Jacqueline L. , Hoog Jeremy , Mashl R. Jay , Wyczalkowski Matthew A. , Mo Chia-Kuei , Liu Ruiyang , Herndon John M. , Davies Sherri R. , Liu Di , Ding Xi , Evrard Yvonne A. , Welm Bryan E. , Lum David , Koh Mei Yee , Welm Alana L. , Chuang Jeffrey H. , Moscow Jeffrey A. , Meric-Bernstam Funda , Govindan Ramaswamy , Li Shunqiang , Hsieh James , Fields Ryan C. , Lim Kian-Huat , Ma Cynthia X. , Zhang Hui , Ding Li , Chen Feng
Published: December 2023

Tumor size and body weight measurements by day
Supplementary Table S9 from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: December 2023

Supplementary Table S9
RPPA data from MRTX-849/SHP099-resistant tumor nodules in KCL mice
Table S1. LILRB1-4 surface expression in AML patient samples from LILRB3 Modulates Acute Myeloid Leukemia Progression and Acts as an Effective Target for CAR T-cell Therapy
Authors: Mai Sunny , Hodges Alan , Chen Hui-Ming , Zhang Jilu , Wang Yi-Ling , Liu Yongbin , Nakatsu Fumiko , Wang Xiaoxuan , Fang Jing , Xu Yitian , Davidov Vitaliy , Kang Kyeongah , Pingali Sai Ravi , Ganguly Siddhartha , Suzuki Masataka , Konopleva Marina , Prinzing Brooke , Zu Youli , Gottschalk Stephen , Lu Yong , Chen Shu-Hsia , Pan Ping-Ying
Published: December 2023

Percent LILRB1-4 positive cells in human AML PBMC. Gated on viable CD33+ cells
Supplementary Table S8 from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: December 2023

Supplementary Table S8
RNA-seq analysis of MTRX-849/SHP099-resistant tumor nodules from KCL mice
Supplementary Data from LILRB3 Modulates Acute Myeloid Leukemia Progression and Acts as an Effective Target for CAR T-cell Therapy
Authors: Mai Sunny , Hodges Alan , Chen Hui-Ming , Zhang Jilu , Wang Yi-Ling , Liu Yongbin , Nakatsu Fumiko , Wang Xiaoxuan , Fang Jing , Xu Yitian , Davidov Vitaliy , Kang Kyeongah , Pingali Sai Ravi , Ganguly Siddhartha , Suzuki Masataka , Konopleva Marina , Prinzing Brooke , Zu Youli , Gottschalk Stephen , Lu Yong , Chen Shu-Hsia , Pan Ping-Ying
Published: December 2023

Supplemental Figure Captions
Supplementary Table S7 from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: December 2023

Supplementary Table S7
RPPA from MTRX-849-resistant tumor nodules from KCL mice
Supplementary Table S6 from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: December 2023

Supplementary Table S6
RNA-seq analysis of MTRX-849-resistant tumor nodules from KCL mice
Supplementary Table S1 from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: December 2023

Supplementary Table S1
MaGeCK analysis of MRTX-849 CRISPR/Cas9 SL screens of NSCLC cell lines
Supplementary Figure Legend from Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Mukhopadhyay Suman , Huang Hsin-Yi , Lin Ziyan , Ranieri Michela , Li Shuai , Sahu Soumyadip , Liu Yingzhuo , Ban Yi , Guidry Kayla , Hu Hai , Lopez Alfonso , Sherman Fiona , Tan Yi Jer , Lee Yeuan Ting , Armstrong Amanda P. , Dolgalev Igor , Sahu Priyanka , Zhang Tinghu , Lu Wenchao , Gray Nathanael S. , Christensen James G. , Tang Tracy T. , Velcheti Vamsidhar , Khodadadi-Jamayran Alireza , Wong Kwok-Kin , Neel Benjamin G.
Published: December 2023

Supplementary Figure Legends
Data from RETRACTED: Physical and Functional Interaction of DNA Methyltransferase 3A with Mbd3 and Brg1 in Mouse Lymphosarcoma Cells
Authors: Datta Jhrana , Majumder Sarmila , Bai Shoumei , Ghoshal Kalpana , Kutay Huban , Smith David Spencer , Crabb John W. , Jacob Samson T.
Published: December 2023

Abstract
Dnmt3a and Dnmt3b are de novo DNA methyltransferases that also act as transcriptional repressors independent of methyltransferase activity. To elucidate the underlying mechanism of transcriptional repression, Dnmt3a was purified from mouse lymphosarcoma cells (P1798) by extensive fractionation on five different chromatographic matrices followed by glycerol density gradient centrifugation. Liquid chromatography electrospray tandem mass spectrometry analysis of Dnmt3a-associated polypeptides identified the methyl CpG binding protein Mbd3, histone deacetylase 1(Hdac1), and components of Brg1 complex (Brg1, Baf155, and Baf57) in the purified preparation. Association of Dnmt3a with Mbd3 and Brg1 was confirmed by coimmunoprecipitation and coimmunolocalization studies. Glutathione S-transferase pulldown assay showed that the NH2-terminal ATRX homology domain of Dnmt3a interacts with the methyl CpG binding domain of Mbd3 and with both bromo and ATPase domains of Brg1. Chromatin immunoprecipitation assay revealed that all three proteins are associated with transcriptionally silent methylated metallothionein (MT-I) promoter in the mouse lymphosarcoma cells. To understand the functional significance of their association with the promoter, their role on the MT-I promoter activity was analyzed by transient transfection assay. The results showed that Mbd3 and Dnmt3a specifically inhibited the methylated promoter, and the catalytic activity of Dnmt3a was dispensable for the suppression. In contrast, the wild-type but not the ATPase-inactive mutant of Brg1 suppressed MT-I promoter irrespective of its methylation status, implicating involvement of ATP-dependent chromatin remodeling in the process. Coexpression of two of the three interacting proteins at a time augmented their repressor function. This study shows physical and functional interaction of Dnmt3a with components of nucleosome remodeling machinery.
Data from RETRACTED: A New Class of Quinoline-Based DNA Hypomethylating Agents Reactivates Tumor Suppressor Genes by Blocking DNA Methyltransferase 1 Activity and Inducing Its Degradation
Authors: Datta Jharna , Ghoshal Kalpana , Denny William A. , Gamage Swarna A. , Brooke Darby G. , Phiasivongsa Pasit , Redkar Sanjeev , Jacob Samson T.
Published: December 2023

Abstract
Reactivation of silenced tumor suppressor genes by 5-azacytidine (Vidaza) and its congener 5-aza-2′-deoxycytidine (decitabine) has provided an alternate approach to cancer therapy. We have shown previously that these drugs selectively and rapidly induce degradation of the maintenance DNA methyltransferase (DNMT) 1 by a proteasomal pathway. Because the toxicity of these compounds is largely due to their incorporation into DNA, it is critical to explore novel, nonnucleoside compounds that can effectively reactivate the silenced genes. Here, we report that a quinoline-based compound, designated SGI-1027, inhibits the activity of DNMT1, DNMT3A, and DNMT3B as well M. SssI with comparable IC50 (6-13 μmol/L) by competing with S-adenosylmethionine in the methylation reaction. Treatment of different cancer cell lines with SGI-1027 resulted in selective degradation of DNMT1 with minimal or no effects on DNMT3A and DNMT3B. At a concentration of 2.5 to 5 μmol/L (similar to that of decitabine), complete degradation of DNMT1 protein was achieved within 24 h without significantly affecting its mRNA level. MG132 blocked SGI-1027–induced depletion of DNMT1, indicating the involvement of proteasomal pathway. Prolonged treatment of RKO cells with SGI-1027 led to demethylation and reexpression of the silenced tumor suppressor genes P16, MLH1, and TIMP3. Further, this compound did not exhibit significant toxicity in a rat hepatoma (H4IIE) cell line. This study provides a novel class of DNA hypomethylating agents that have the potential for use in epigenetic cancer therapy. [Cancer Res 2009;69(10):4277–85]
Data from Combining the Tyrosine Kinase Inhibitor Cabozantinib and the mTORC1/2 Inhibitor Sapanisertib Blocks ERK Pathway Activity and Suppresses Tumor Growth in Renal Cell Carcinoma
Authors: Wu Yige , Chen Siqi , Yang Xiaolu , Sato Kazuhito , Lal Preet , Wang Yuefan , Shinkle Andrew T. , Wendl Michael C. , Primeau Tina M. , Zhao Yanyan , Gould Alanna , Sun Hua , Mudd Jacqueline L. , Hoog Jeremy , Mashl R. Jay , Wyczalkowski Matthew A. , Mo Chia-Kuei , Liu Ruiyang , Herndon John M. , Davies Sherri R. , Liu Di , Ding Xi , Evrard Yvonne A. , Welm Bryan E. , Lum David , Koh Mei Yee , Welm Alana L. , Chuang Jeffrey H. , Moscow Jeffrey A. , Meric-Bernstam Funda , Govindan Ramaswamy , Li Shunqiang , Hsieh James , Fields Ryan C. , Lim Kian-Huat , Ma Cynthia X. , Zhang Hui , Ding Li , Chen Feng
Published: December 2023

Abstract
Current treatment approaches for renal cell carcinoma (RCC) face challenges in achieving durable tumor responses due to tumor heterogeneity and drug resistance. Combination therapies that leverage tumor molecular profiles could offer an avenue for enhancing treatment efficacy and addressing the limitations of current therapies. To identify effective strategies for treating RCC, we selected ten drugs guided by tumor biology to test in six RCC patient-derived xenograft (PDX) models. The multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and mTORC1/2 inhibitor sapanisertib emerged as the most effective drugs, particularly when combined. The combination demonstrated favorable tolerability and inhibited tumor growth or induced tumor regression in all models, including two from patients who experienced treatment failure with FDA-approved TKI and immunotherapy combinations. In cabozantinib-treated samples, imaging analysis revealed a significant reduction in vascular density, and single-nucleus RNA sequencing (snRNA-seq) analysis indicated a decreased proportion of endothelial cells in the tumors. SnRNA-seq data further identified a tumor subpopulation enriched with cell-cycle activity that exhibited heightened sensitivity to the cabozantinib and sapanisertib combination. Conversely, activation of the epithelial–mesenchymal transition pathway, detected at the protein level, was associated with drug resistance in residual tumors following combination treatment. The combination effectively restrained ERK phosphorylation and reduced expression of ERK downstream transcription factors and their target genes implicated in cell-cycle control and apoptosis. This study highlights the potential of the cabozantinib plus sapanisertib combination as a promising treatment approach for patients with RCC, particularly those whose tumors progressed on immune checkpoint inhibitors and other TKIs.
Significance:
The molecular-guided therapeutic strategy of combining cabozantinib and sapanisertib restrains ERK activity to effectively suppress growth of renal cell carcinomas, including those unresponsive to immune checkpoint inhibitors.
Data from CRISPR Screening Identifies Mechanisms of Resistance to KRASG12C and SHP2 Inhibitor Combinations in Non–Small Cell Lung Cancer
Authors: Prahallad Anirudh , Weiss Andreas , Voshol Hans , Kerr Grainne , Sprouffske Kathleen , Yuan Tina , Ruddy David , Meistertzheim Morgane , Kazic-Legueux Malika , Kottarathil Tina , Piquet Michelle , Cao Yichen , Martinuzzi-Duboc Laetitia , Buhles Alexandra , Adler Flavia , Mannino Salvatore , Tordella Luca , Sansregret Laurent , Maira Sauveur-Michel , Graus Porta Diana , Fedele Carmine , Brachmann Saskia M.
Published: December 2023

Abstract
Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non–small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the cyclin-dependent kinase 4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Tumor regression by single-agent JDQ443 at clinically relevant doses lasted on average 2 weeks and was increasingly extended by the double, triple, or quadruple combinations. Growth resumption was accompanied by progressively increased KRAS G12C amplification. Functional genome-wide CRISPR screening in KRASG12C-dependent NSCLC lines with distinct mutational profiles to identify adaptive mechanisms of resistance revealed sensitizing and rescuing genetic interactions with KRASG12C/SHP2 coinhibition; FGFR1 loss was the strongest sensitizer, and PTEN loss the strongest rescuer. Consistently, the antiproliferative activity of KRASG12C/SHP2 inhibition was strongly enhanced by PI3K inhibitors. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments.
Significance:
Identification of resistance mechanisms to KRASG12C/SHP2 coinhibition highlights the need for additional combination therapies for lung cancer beyond on-pathway combinations and offers the basis for development of more effective combination approaches.

See related commentary by Johnson and Haigis, p. 4005