ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

Nicholas R. Jette; Suraj Radhamani; Ruiqiong Ye; Yaping Yu; Greydon Arthur; Siddhartha Goutam; Tarek A. Bismar; Mehul Kumar; Pinaki Bose; Steven Yip; Michael Kolinsky; Susan P. Lees-Miller

doi:10.1007/s42764-020-00011-0

Genome Instability & Disease ›› 2020, Vol. 1 ›› Issue (4) : 197-205. DOI: 10.1007/s42764-020-00011-0

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ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

Nicholas R. Jette¹^,²^,⁵ ,
Suraj Radhamani¹^,²^,⁵ ,
Ruiqiong Ye¹^,²^,⁵ ,
Yaping Yu¹^,²^,⁵ ,
Greydon Arthur¹^,²^,⁵ ,
Siddhartha Goutam¹^,²^,⁵ ,
Tarek A. Bismar¹^,³^,⁴^,⁵^,⁶ ,
Mehul Kumar¹^,⁵ ,
Pinaki Bose¹^,³^,⁵ ,
Steven Yip³^,⁵^,⁶ ,
Michael Kolinsky⁷ ,
Susan P. Lees-Miller¹^,²^,³^,⁵^,ⁿ

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Abstract

The Ataxia Telangiectasia Mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP-ribose polymerase (PARP) inhibitor olaparib induces transient G2 arrest but not cell death in ATM-deficient lung cancer cells, while the combination of olaparib with the ATM- and Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that combination of olaparib plus the clinically relevant ATR inhibitor AZD6738 also induces cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts. Together, our data suggest that lung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

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Nicholas R. Jette, Suraj Radhamani, Ruiqiong Ye, Yaping Yu, Greydon Arthur, Siddhartha Goutam, Tarek A. Bismar, Mehul Kumar, Pinaki Bose, Steven Yip, Michael Kolinsky, Susan P. Lees-Miller. ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738. Genome Instability & Disease, 2020, 1(4): 197‒205 https://doi.org/10.1007/s42764-020-00011-0