KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

Yuanwang Pan; Han Han; Hai Hu; Hua Wang; Yueqiang Song; Yuan Hao; Xinyuan Tong; Ayushi S. Patel; Selim Misirlioglu; Sittinon Tang; Hsin Yi Huang; Ke Geng; Ting Chen; Angeliki Karatza; Fiona Sherman; Kristen E. Labbe; Fan Yang; Alison Chafitz; Chengwei Peng; Chenchen Guo; Andre L. Moreira; Vamsidhar Velcheti; Sally C.M. Lau; Pengfei Sui; Haiquan Chen; J. Alan Diehl; Anil K. Rustgi; Adam J. Bass; John T. Poirier; Xiaoyang Zhang; Hongbin Ji; Hua Zhang; Kwok Kin Wong

doi:10.1016/j.ccell.2022.11.015

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

Yuanwang Pan, Han Han, Hai Hu, Hua Wang, Yueqiang Song, Yuan Hao, Xinyuan Tong, Ayushi S. Patel, Selim Misirlioglu, Sittinon Tang, Hsin Yi Huang, Ke Geng, Ting Chen, Angeliki Karatza, Fiona Sherman, Kristen E. Labbe, Fan Yang, Alison Chafitz, Chengwei Peng, Chenchen GuoAndre L. Moreira, Vamsidhar Velcheti, Sally C.M. Lau, Pengfei Sui, Haiquan Chen, J. Alan Diehl, Anil K. Rustgi, Adam J. Bass, John T. Poirier, Xiaoyang Zhang, Hongbin Ji^*, Hua Zhang^*, Kwok Kin Wong^*

^*Corresponding author for this work

Medicine, Hematology Oncology Division

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

Original language	English (US)
Pages (from-to)	88-105.e8
Journal	Cancer cell
Volume	41
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2022.11.015
State	Published - Jan 9 2023

Funding

We thank NYU Langone Preclinical Imaging Laboratory (partially funded by P30CA016087 and P41 EB017183 ) for MRI; the Genome Technology Center (partially supported by P30CA016087 ) for library preparation and sequencing; and the Experimental Pathology Research Laboratory (partially funded by P30CA016087 ) for immunohistochemistry. This work is supported by U01 CA233084 (K.-K.W.); R01 CA219670 (K.-K.W.); R01 CA216188 (K.-K.W.); R01 CA205150 (K.-K.W.); R01 CA166480 (K.-K.W.); P01 CA154303 (K.-K.W.); P01 CA098101 (A.K.R., A.J.B., J.A.D., and K.-K.W.; and the Molecular Pathology and Biostatistics Shared Resources ); P30 CA013696 (A.K.R.); and the International Cooperation Project of Chinese Academy of Sciences 153D31KYSB20190035 (H.J.).

Keywords

EGFR
ERBB2
KMT2D
SHP2
lung squamous cell carcinoma
organoids

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2022.11.015

Cite this

Pan, Y., Han, H., Hu, H., Wang, H., Song, Y., Hao, Y., Tong, X., Patel, A. S., Misirlioglu, S., Tang, S., Huang, H. Y., Geng, K., Chen, T., Karatza, A., Sherman, F., Labbe, K. E., Yang, F., Chafitz, A., Peng, C., ... Wong, K. K. (2023). KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition. Cancer cell, 41(1), 88-105.e8. https://doi.org/10.1016/j.ccell.2022.11.015

@article{7c4b2d922548481696c0672a2b0af3b4,

title = "KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition",

abstract = "Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.",

keywords = "EGFR, ERBB2, KMT2D, SHP2, lung squamous cell carcinoma, organoids",

author = "Yuanwang Pan and Han Han and Hai Hu and Hua Wang and Yueqiang Song and Yuan Hao and Xinyuan Tong and Patel, {Ayushi S.} and Selim Misirlioglu and Sittinon Tang and Huang, {Hsin Yi} and Ke Geng and Ting Chen and Angeliki Karatza and Fiona Sherman and Labbe, {Kristen E.} and Fan Yang and Alison Chafitz and Chengwei Peng and Chenchen Guo and Moreira, {Andre L.} and Vamsidhar Velcheti and Lau, {Sally C.M.} and Pengfei Sui and Haiquan Chen and Diehl, {J. Alan} and Rustgi, {Anil K.} and Bass, {Adam J.} and Poirier, {John T.} and Xiaoyang Zhang and Hongbin Ji and Hua Zhang and Wong, {Kwok Kin}",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2023",

month = jan,

day = "9",

doi = "10.1016/j.ccell.2022.11.015",

language = "English (US)",

volume = "41",

pages = "88--105.e8",

journal = "Cancer cell",

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Pan, Y, Han, H, Hu, H, Wang, H, Song, Y, Hao, Y, Tong, X, Patel, AS, Misirlioglu, S, Tang, S, Huang, HY, Geng, K, Chen, T, Karatza, A, Sherman, F, Labbe, KE, Yang, F, Chafitz, A, Peng, C, Guo, C, Moreira, AL, Velcheti, V, Lau, SCM, Sui, P, Chen, H, Diehl, JA, Rustgi, AK, Bass, AJ, Poirier, JT, Zhang, X, Ji, H, Zhang, H & Wong, KK 2023, 'KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition', Cancer cell, vol. 41, no. 1, pp. 88-105.e8. https://doi.org/10.1016/j.ccell.2022.11.015

TY - JOUR

T1 - KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

AU - Pan, Yuanwang

AU - Han, Han

AU - Hu, Hai

AU - Wang, Hua

AU - Song, Yueqiang

AU - Hao, Yuan

AU - Tong, Xinyuan

AU - Patel, Ayushi S.

AU - Misirlioglu, Selim

AU - Tang, Sittinon

AU - Huang, Hsin Yi

AU - Geng, Ke

AU - Chen, Ting

AU - Karatza, Angeliki

AU - Sherman, Fiona

AU - Labbe, Kristen E.

AU - Yang, Fan

AU - Chafitz, Alison

AU - Peng, Chengwei

AU - Guo, Chenchen

AU - Moreira, Andre L.

AU - Velcheti, Vamsidhar

AU - Lau, Sally C.M.

AU - Sui, Pengfei

AU - Chen, Haiquan

AU - Diehl, J. Alan

AU - Rustgi, Anil K.

AU - Bass, Adam J.

AU - Poirier, John T.

AU - Zhang, Xiaoyang

AU - Ji, Hongbin

AU - Zhang, Hua

AU - Wong, Kwok Kin

PY - 2023/1/9

Y1 - 2023/1/9

N2 - Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

AB - Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

KW - EGFR

KW - ERBB2

KW - KMT2D

KW - SHP2

KW - lung squamous cell carcinoma

KW - organoids

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DO - 10.1016/j.ccell.2022.11.015

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AN - SCOPUS:85146037855

SN - 1535-6108

VL - 41

SP - 88-105.e8

JO - Cancer cell

JF - Cancer cell

IS - 1

ER -

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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