Tar­get­ing a Po­ten­tial Vul­ner­a­bil­i­ty of Cer­tain Can­cers with DNA Dam­age Re­sponse

Every in­di­vid­ual’s DNA is unique, and be­cause of this, every pa­tient re­sponds dif­fer­ent­ly to dis­ease and treat­ment. It is as­ton­ish­ing how four tiny build­ing blocks of our DNA – A, T, C, G – dic­tate our health, dis­ease, and how we age.

The tricky thing about DNA is that it is con­stant­ly ex­posed to dam­age by sources such as ul­tra­vi­o­let light, cer­tain chem­i­cals, tox­ins, and even nat­ur­al bio­chem­i­cal process­es in­side our cells.¹ If ig­nored, DNA dam­age will ac­cu­mu­late in repli­cat­ing cells, giv­ing rise to mu­ta­tions that can lead to pre­ma­ture ag­ing, can­cer, and oth­er dis­eases.

To com­bat DNA dam­age, our cells have a com­plex net­work called DNA dam­age re­sponse (DDR), which is re­spon­si­ble for sens­ing and re­pair­ing DNA en­sur­ing ge­nom­ic in­tegri­ty and cell sur­vival. This high­ly or­ga­nized net­work de­tects dam­age and sig­nals the pres­ence of DNA dam­age to a com­plex re­pair ma­chin­ery.² If dam­age is not cor­rect­ed, or be­comes too sub­stan­tial to over­come, cells can ini­ti­ate a process of pro­grammed cell death called apop­to­sis.³ By do­ing so, they min­i­mize the risk of prop­a­gat­ing dan­ger­ous mu­ta­tions, which could po­ten­tial­ly trans­form healthy cells in­to can­cer­ous cells.

In can­cer, DDR be­comes crit­i­cal. Cells with de­fects in their DNA re­pair ma­chin­ery fail to pre­serve their ge­net­ic in­tegri­ty, and the ac­cu­mu­la­tion of mu­ta­tions and ge­net­ic in­sta­bil­i­ty is a well-rec­og­nized hall­mark of can­cer.⁴ Tu­mor cells of­ten have mu­ta­tions in one of their DNA re­pair path­ways. This al­lows them to de­vel­op mu­ta­tions in onco­genes, tu­mor sup­pres­sors or drug tar­gets and there­by evade treat­ment, yet at the same time, makes them vul­ner­a­ble.² One nov­el con­cept tak­ing ad­van­tage of faulty DDR in can­cer cells is syn­thet­ic lethal­i­ty.

Syn­thet­ic lethal­i­ty oc­curs when two con­cur­rent path­way dis­rup­tions (for ex­am­ple, a ge­net­ic aber­ra­tion and a phar­ma­co­log­i­cal in­ter­ven­tion) dis­able a can­cer cell’s abil­i­ty to re­pair DNA dam­age, re­sult­ing in its death, while nor­mal cells with in­tact DDR path­ways can com­pen­sate for the phar­ma­co­log­i­cal block­ade.⁵,⁶ Learn­ing how to ex­ploit these vul­ner­a­bil­i­ties may en­able tar­get­ing of the ‘Achilles’ heel’ of spe­cif­ic can­cers.

At Mer­ck KGaA, Darm­stadt, Ger­many, our cu­rios­i­ty to trans­form can­cer care dri­ves us to un­der­stand and ex­plore the full po­ten­tial of promis­ing mech­a­nisms in can­cer re­search. DDR is one of our key mech­a­nis­tic pil­lars of fo­cus in on­col­o­gy, and we be­lieve it has the po­ten­tial to trans­form stan­dard can­cer care both as monother­a­py, and in com­bi­na­tion with im­munother­a­py, chemother­a­py or ra­dio­ther­a­py.

Ini­tial­ly, we are fo­cus­ing on three tar­gets that play im­por­tant roles across sev­er­al DDR path­ways, atax­ia telang­iec­ta­sia RAD3 re­lat­ed (ATR), atax­ia telang­iec­ta­sia mu­tat­ed (ATM), and DNA-de­pen­dent pro­tein ki­nas­es (DNA-PK). We have in­vest­ed sig­nif­i­cant re­sources in­to this promis­ing ap­proach with a fo­cus on syn­thet­ic lethal­i­ty, im­mune ac­ti­va­tion, and in­duced DNA dam­age. In 2017, we boost­ed our in-house ex­per­tise and ca­pa­bil­i­ties, and li­censed two DDR clin­i­cal-stage pro­grams (an ATR and DNA-PK pro­gram) and two nov­el pre-clin­i­cal pro­grams. More re­cent­ly, in 2020, we em­barked on a col­lab­o­ra­tion with Ar­tios Phar­ma, a lead­ing DDR com­pa­ny, and will use their DNA nu­cle­ase plat­form to iden­ti­fy nov­el in­hibitors against this tar­get class and syn­thet­ic lethal in­ter­ac­tions to guide their op­ti­mal clin­i­cal de­vel­op­ment, fur­ther pro­mot­ing syn­er­gy of our knowl­edge and ex­per­tise in this promis­ing field.

Take, for ex­am­ple, tu­mor cells that have non-func­tion­al ATM, which makes them more de­pen­dent on the ATR re­pair path­way.⁷ In­hibitors of ATR may have po­ten­tial as monother­a­py against tu­mors with ATM loss-of-func­tion. Fur­ther­more, ATR is es­sen­tial to man­age high repli­ca­tion stress, for in­stance caused by cer­tain onco­genes, po­ten­tial­ly mak­ing cor­re­spond­ing tu­mors vul­ner­a­ble to ATR in­hibitors. Fi­nal­ly, when used in com­bi­na­tion with chemother­a­py or ra­di­a­tion, ATR in­hibitors may po­ten­tial­ly en­hance the ef­fi­ca­cy of these DNA-dam­ag­ing agents.

Our lead DDR in­hibitor can­di­date is a first-in-class ATR in­hibitor. Pre-clin­i­cal da­ta demon­strate that by en­hanc­ing repli­ca­tion fork col­lapse in sol­id tu­mor cells, it may sen­si­tize can­cer cells to DNA-dam­ag­ing drugs.⁷ This is the first ATR in­hibitor in a ran­dom­ized clin­i­cal tri­al in any tu­mor type, and it is cur­rent­ly be­ing in­ves­ti­gat­ed in a num­ber of stud­ies with ear­ly phase I/II da­ta in small cell lung can­cer, ovar­i­an can­cer, colon can­cer, and var­i­ous sol­id tu­mors.⁸,⁹

At Mer­ck KGaA, Darm­stadt, Ger­many, we are in­spired by our pa­tients who give us pur­pose every day. We con­tin­ue to ex­plore the com­plex­i­ties of the ge­net­ic code of tu­mors, and are con­fi­dent that we are on the hori­zon of bring­ing in­no­v­a­tive ther­a­peu­tic so­lu­tions to the field of on­col­o­gy. Learn more here.

EMD Serono is the bio­phar­ma­ceu­ti­cal busi­ness of Mer­ck KGaA, Darm­stadt, Ger­many, in the Unit­ed States and Cana­da. US-NONO-00121

Ref­er­ences:

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2. Jack­son, S., Bartek, J. (2009). The DNA-dam­age re­sponse in hu­man bi­ol­o­gy and dis­ease. Na­ture. Avail­able from: https://doi.org/10.1038/na­ture08467
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