Targeting aberrant replication and DNA repair events for treating breast cancers

Subapriya Rajamanickam; Jun Hyoung Park; Panneerdoss Subbarayalu; Santosh Timilsina; Kaitlyn Bates; Pooja Yadav; Saif S.R. Nirzhor; Vijay Eedunuri; Tabrez A. Mohammad; Kwang Hwa Jung; Benjamin Onyeagucha; Nourhan Abdelfattah; Raymond Benevides; Grace Lee; Yidong Chen; Ratna Vadlamudi; Andrew Brenner; Virginia Kaklamani; Ismail Jatoi; John Kuhn; Robert Hromas; Yogesh K. Gupta; Benny A. Kaipparettu; Jack L. Arbiser; Manjeet K. Rao

doi:10.1038/s42003-022-03413-w

Targeting aberrant replication and DNA repair events for treating breast cancers

Subapriya Rajamanickam, Jun Hyoung Park, Panneerdoss Subbarayalu, Santosh Timilsina, Kaitlyn Bates, Pooja Yadav, Saif S.R. Nirzhor, Vijay Eedunuri, Tabrez A. Mohammad, Kwang Hwa Jung, Benjamin Onyeagucha, Nourhan Abdelfattah, Raymond Benevides, Grace Lee, Yidong Chen, Ratna Vadlamudi, Andrew Brenner, Virginia Kaklamani, Ismail Jatoi, John KuhnRobert Hromas, Yogesh K. Gupta, Benny A. Kaipparettu, Jack L. Arbiser, Manjeet K. Rao

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2 Scopus citations

Abstract

The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.

Original language	English (US)
Article number	493
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03413-w
State	Published - Dec 2022

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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Rajamanickam, S., Park, J. H., Subbarayalu, P., Timilsina, S., Bates, K., Yadav, P., Nirzhor, S. S. R., Eedunuri, V., Mohammad, T. A., Jung, K. H., Onyeagucha, B., Abdelfattah, N., Benevides, R., Lee, G., Chen, Y., Vadlamudi, R., Brenner, A., Kaklamani, V., Jatoi, I., ... Rao, M. K. (2022). Targeting aberrant replication and DNA repair events for treating breast cancers. Communications Biology, 5(1), Article 493. https://doi.org/10.1038/s42003-022-03413-w

Rajamanickam, S, Park, JH, Subbarayalu, P, Timilsina, S, Bates, K, Yadav, P, Nirzhor, SSR, Eedunuri, V, Mohammad, TA, Jung, KH, Onyeagucha, B, Abdelfattah, N, Benevides, R, Lee, G, Chen, Y , Vadlamudi, R , Brenner, A , Kaklamani, V , Jatoi, I, Kuhn, J, Hromas, R , Gupta, YK, Kaipparettu, BA, Arbiser, JL & Rao, MK 2022, 'Targeting aberrant replication and DNA repair events for treating breast cancers', Communications Biology, vol. 5, no. 1, 493. https://doi.org/10.1038/s42003-022-03413-w

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title = "Targeting aberrant replication and DNA repair events for treating breast cancers",

abstract = "The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.",

author = "Subapriya Rajamanickam and Park, {Jun Hyoung} and Panneerdoss Subbarayalu and Santosh Timilsina and Kaitlyn Bates and Pooja Yadav and Nirzhor, {Saif S.R.} and Vijay Eedunuri and Mohammad, {Tabrez A.} and Jung, {Kwang Hwa} and Benjamin Onyeagucha and Nourhan Abdelfattah and Raymond Benevides and Grace Lee and Yidong Chen and Ratna Vadlamudi and Andrew Brenner and Virginia Kaklamani and Ismail Jatoi and John Kuhn and Robert Hromas and Gupta, {Yogesh K.} and Kaipparettu, {Benny A.} and Arbiser, {Jack L.} and Rao, {Manjeet K.}",

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doi = "10.1038/s42003-022-03413-w",

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AU - Rajamanickam, Subapriya

AU - Park, Jun Hyoung

AU - Subbarayalu, Panneerdoss

AU - Timilsina, Santosh

AU - Bates, Kaitlyn

AU - Yadav, Pooja

AU - Nirzhor, Saif S.R.

AU - Eedunuri, Vijay

AU - Mohammad, Tabrez A.

AU - Jung, Kwang Hwa

AU - Onyeagucha, Benjamin

AU - Abdelfattah, Nourhan

AU - Benevides, Raymond

AU - Lee, Grace

AU - Chen, Yidong

AU - Vadlamudi, Ratna

AU - Brenner, Andrew

AU - Kaklamani, Virginia

AU - Jatoi, Ismail

AU - Kuhn, John

AU - Hromas, Robert

AU - Gupta, Yogesh K.

AU - Kaipparettu, Benny A.

AU - Arbiser, Jack L.

AU - Rao, Manjeet K.

PY - 2022/12

Y1 - 2022/12

N2 - The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.

AB - The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.

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Targeting aberrant replication and DNA repair events for treating breast cancers

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