PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

Pedro Torres-Ayuso; Meghri Katerji; Dawid Mehlich; Sophia A. Lookingbill; Venkata R. Sabbasani; Hope Liou; Andrea L. Casillas; Shailender S. Chauhan; Remigiusz Serwa; Maxine R. Rubin; Anna A. Marusiak; Rolf E. Swenson; Noel A. Warfel; John Brognard

doi:10.1016/j.chembiol.2023.10.023

PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

Pedro Torres-Ayuso, Meghri Katerji, Dawid Mehlich, Sophia A. Lookingbill, Venkata R. Sabbasani, Hope Liou, Andrea L. Casillas, Shailender S. Chauhan, Remigiusz Serwa, Maxine R. Rubin, Anna A. Marusiak, Rolf E. Swenson, Noel A. Warfel, John Brognard

Cancer Signaling and Microenvironment (CSM)

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

4 Scopus citations

Abstract

PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

Original language	English
Pages (from-to)	326-337.e11
Journal	Cell Chemical Biology
Volume	31
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2023.10.023
State	Published - Feb 15 2024

Keywords

PIM kinases
PROTAC
chemoresistance
prostate cancer
proteolysis
targeted therapeutics

UN SDGs

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

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10.1016/j.chembiol.2023.10.023

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Torres-Ayuso, P., Katerji, M., Mehlich, D., Lookingbill, S. A., Sabbasani, V. R., Liou, H., Casillas, A. L., Chauhan, S. S., Serwa, R., Rubin, M. R., Marusiak, A. A., Swenson, R. E., Warfel, N. A., & Brognard, J. (2024). PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer. Cell Chemical Biology, 31(2), 326-337.e11. https://doi.org/10.1016/j.chembiol.2023.10.023

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title = "PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer",

abstract = "PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.",

keywords = "PIM kinases, PROTAC, chemoresistance, prostate cancer, proteolysis, targeted therapeutics",

author = "Pedro Torres-Ayuso and Meghri Katerji and Dawid Mehlich and Lookingbill, {Sophia A.} and Sabbasani, {Venkata R.} and Hope Liou and Casillas, {Andrea L.} and Chauhan, {Shailender S.} and Remigiusz Serwa and Rubin, {Maxine R.} and Marusiak, {Anna A.} and Swenson, {Rolf E.} and Warfel, {Noel A.} and John Brognard",

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Torres-Ayuso, P, Katerji, M, Mehlich, D, Lookingbill, SA, Sabbasani, VR, Liou, H, Casillas, AL, Chauhan, SS, Serwa, R, Rubin, MR, Marusiak, AA, Swenson, RE, Warfel, NA & Brognard, J 2024, 'PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer', Cell Chemical Biology, vol. 31, no. 2, pp. 326-337.e11. https://doi.org/10.1016/j.chembiol.2023.10.023

TY - JOUR

T1 - PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

AU - Torres-Ayuso, Pedro

AU - Katerji, Meghri

AU - Mehlich, Dawid

AU - Lookingbill, Sophia A.

AU - Sabbasani, Venkata R.

AU - Liou, Hope

AU - Casillas, Andrea L.

AU - Chauhan, Shailender S.

AU - Serwa, Remigiusz

AU - Rubin, Maxine R.

AU - Marusiak, Anna A.

AU - Swenson, Rolf E.

AU - Warfel, Noel A.

AU - Brognard, John

PY - 2024/2/15

Y1 - 2024/2/15

N2 - PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

AB - PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity at inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

KW - PIM kinases

KW - PROTAC

KW - chemoresistance

KW - prostate cancer

KW - proteolysis

KW - targeted therapeutics

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UR - https://pubmed.ncbi.nlm.nih.gov/38016478/

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DO - 10.1016/j.chembiol.2023.10.023

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AN - SCOPUS:85180311125

SN - 2451-9456

VL - 31

SP - 326-337.e11

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 2

ER -

PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

Abstract

Keywords

UN SDGs

Access to Document

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Findings from National Cancer Institute (NCI) in Prostate Cancer Reported (Pim1 Targeted Degradation Prevents the Emergence of Chemoresistance In Prostate Cancer)

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PIM1 targeted degradation prevents the emergence of chemoresistance in prostate cancer

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Press/Media

Findings from National Cancer Institute (NCI) in Prostate Cancer Reported (Pim1 Targeted Degradation Prevents the Emergence of Chemoresistance In Prostate Cancer)

Cite this