Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression

Darshan S. Chandrashekar; Balabhadrapatruni V.S.K. Chakravarthi; Alyncia D. Robinson; Joshua C. Anderson; Sumit Agarwal; Sai Akshaya Hodigere Balasubramanya; Marie Lisa Eich; Akhilesh Kumar Bajpai; Sravanthi Davuluri; Maya S. Guru; Arjun S. Guru; Gurudatta Naik; Deborah L. Della Manna; Kshitish K. Acharya; Shannon Carskadon; Upender Manne; David K. Crossman; James E. Ferguson; William E. Grizzle; Nallasivam Palanisamy; Christopher D. Willey; Michael R. Crowley; George J. Netto; Eddy S. Yang; Sooryanarayana Varambally; Guru Sonpavde

doi:10.1038/s41388-020-1275-7

Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression

Darshan S. Chandrashekar, Balabhadrapatruni V.S.K. Chakravarthi, Alyncia D. Robinson, Joshua C. Anderson, Sumit Agarwal, Sai Akshaya Hodigere Balasubramanya, Marie Lisa Eich, Akhilesh Kumar Bajpai, Sravanthi Davuluri, Maya S. Guru, Arjun S. Guru, Gurudatta Naik, Deborah L. Della Manna, Kshitish K. Acharya, Shannon Carskadon, Upender Manne, David K. Crossman, James E. Ferguson, William E. Grizzle, Nallasivam PalanisamyChristopher D. Willey, Michael R. Crowley, George J. Netto, Eddy S. Yang, Sooryanarayana Varambally, Guru Sonpavde

Radiation Medicine

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

Abstract

Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

Original language	English
Pages (from-to)	4077-4091
Number of pages	15
Journal	Oncogene
Volume	39
Issue number	20
DOIs	https://doi.org/10.1038/s41388-020-1275-7
State	Published - May 14 2020

Bibliographical note

Funding Information:
Conflict of interest GS was a consultant for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, Astellas/Agensys; Research support to institution from Bayer, Amgen, Boehringer-Ingelheim, Merck, Sanofi, Pfizer; Author for Up-to-date; Speaker for Clinical Care Options, Physicians Education Resource (PER), Research to Practice (RTP), Onclive. CW was a consultant for Varian Medical Systems and LifeNet Health, Inc. AB and SD received financial support from Shodhaka LS Pvt. Ltd. KKA is the founder and director of Shodhaka LS Pvt. Ltd. GJN served as a consultant to Genentec. ESY was a consultant for Astrazeneca; Research support to institution from Astrazeneca, Eli Lilly, Novartis.

Funding Information:
Acknowledgements This study was supported in part by institutional funds (Department of Pathology and School of Medicine of the University of Alabama at Birmingham) awarded to SV. IBAB is supported by the Department of IT, BT and S&T, Government of Karnataka, India. The authors thank Dr Donald Hill for critical reading and editing of this manuscript.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

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

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10.1038/s41388-020-1275-7

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Chandrashekar, D. S., Chakravarthi, B. V. S. K., Robinson, A. D., Anderson, J. C., Agarwal, S., Balasubramanya, S. A. H., Eich, M. L., Bajpai, A. K., Davuluri, S., Guru, M. S., Guru, A. S., Naik, G., Della Manna, D. L., Acharya, K. K., Carskadon, S., Manne, U., Crossman, D. K., Ferguson, J. E., Grizzle, W. E., ... Sonpavde, G. (2020). Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression. Oncogene, 39(20), 4077-4091. https://doi.org/10.1038/s41388-020-1275-7

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title = "Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression",

abstract = "Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.",

author = "Chandrashekar, {Darshan S.} and Chakravarthi, {Balabhadrapatruni V.S.K.} and Robinson, {Alyncia D.} and Anderson, {Joshua C.} and Sumit Agarwal and Balasubramanya, {Sai Akshaya Hodigere} and Eich, {Marie Lisa} and Bajpai, {Akhilesh Kumar} and Sravanthi Davuluri and Guru, {Maya S.} and Guru, {Arjun S.} and Gurudatta Naik and {Della Manna}, {Deborah L.} and Acharya, {Kshitish K.} and Shannon Carskadon and Upender Manne and Crossman, {David K.} and Ferguson, {James E.} and Grizzle, {William E.} and Nallasivam Palanisamy and Willey, {Christopher D.} and Crowley, {Michael R.} and Netto, {George J.} and Yang, {Eddy S.} and Sooryanarayana Varambally and Guru Sonpavde",

note = "Funding Information: Conflict of interest GS was a consultant for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, Astellas/Agensys; Research support to institution from Bayer, Amgen, Boehringer-Ingelheim, Merck, Sanofi, Pfizer; Author for Up-to-date; Speaker for Clinical Care Options, Physicians Education Resource (PER), Research to Practice (RTP), Onclive. CW was a consultant for Varian Medical Systems and LifeNet Health, Inc. AB and SD received financial support from Shodhaka LS Pvt. Ltd. KKA is the founder and director of Shodhaka LS Pvt. Ltd. GJN served as a consultant to Genentec. ESY was a consultant for Astrazeneca; Research support to institution from Astrazeneca, Eli Lilly, Novartis. Funding Information: Acknowledgements This study was supported in part by institutional funds (Department of Pathology and School of Medicine of the University of Alabama at Birmingham) awarded to SV. IBAB is supported by the Department of IT, BT and S&T, Government of Karnataka, India. The authors thank Dr Donald Hill for critical reading and editing of this manuscript. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2020",

month = may,

day = "14",

doi = "10.1038/s41388-020-1275-7",

language = "English",

volume = "39",

pages = "4077--4091",

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Chandrashekar, DS, Chakravarthi, BVSK, Robinson, AD, Anderson, JC, Agarwal, S, Balasubramanya, SAH, Eich, ML, Bajpai, AK, Davuluri, S, Guru, MS, Guru, AS, Naik, G, Della Manna, DL, Acharya, KK, Carskadon, S, Manne, U, Crossman, DK, Ferguson, JE, Grizzle, WE, Palanisamy, N, Willey, CD, Crowley, MR, Netto, GJ, Yang, ES, Varambally, S & Sonpavde, G 2020, 'Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression', Oncogene, vol. 39, no. 20, pp. 4077-4091. https://doi.org/10.1038/s41388-020-1275-7

TY - JOUR

T1 - Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression

AU - Chandrashekar, Darshan S.

AU - Chakravarthi, Balabhadrapatruni V.S.K.

AU - Robinson, Alyncia D.

AU - Anderson, Joshua C.

AU - Agarwal, Sumit

AU - Balasubramanya, Sai Akshaya Hodigere

AU - Eich, Marie Lisa

AU - Bajpai, Akhilesh Kumar

AU - Davuluri, Sravanthi

AU - Guru, Maya S.

AU - Guru, Arjun S.

AU - Naik, Gurudatta

AU - Della Manna, Deborah L.

AU - Acharya, Kshitish K.

AU - Carskadon, Shannon

AU - Manne, Upender

AU - Crossman, David K.

AU - Ferguson, James E.

AU - Grizzle, William E.

AU - Palanisamy, Nallasivam

AU - Willey, Christopher D.

AU - Crowley, Michael R.

AU - Netto, George J.

AU - Yang, Eddy S.

AU - Varambally, Sooryanarayana

AU - Sonpavde, Guru

N1 - Funding Information: Conflict of interest GS was a consultant for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, Astellas/Agensys; Research support to institution from Bayer, Amgen, Boehringer-Ingelheim, Merck, Sanofi, Pfizer; Author for Up-to-date; Speaker for Clinical Care Options, Physicians Education Resource (PER), Research to Practice (RTP), Onclive. CW was a consultant for Varian Medical Systems and LifeNet Health, Inc. AB and SD received financial support from Shodhaka LS Pvt. Ltd. KKA is the founder and director of Shodhaka LS Pvt. Ltd. GJN served as a consultant to Genentec. ESY was a consultant for Astrazeneca; Research support to institution from Astrazeneca, Eli Lilly, Novartis. Funding Information: Acknowledgements This study was supported in part by institutional funds (Department of Pathology and School of Medicine of the University of Alabama at Birmingham) awarded to SV. IBAB is supported by the Department of IT, BT and S&T, Government of Karnataka, India. The authors thank Dr Donald Hill for critical reading and editing of this manuscript. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2020/5/14

Y1 - 2020/5/14

N2 - Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

AB - Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

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Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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