Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA-Associated Pancreatic Cancer in the Clinical and Preclinical Setting
©2023 The Authors; Published by the American Association for Cancer Research..
Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions.
SIGNIFICANCE: glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Cancer discovery - 13(2023), 8 vom: 04. Aug., Seite 1826-1843 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Stossel, Chani [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
49DFR088MY |
|---|
| Anmerkungen: |
Date Completed 07.08.2023 Date Revised 13.12.2023 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1158/2159-8290.CD-22-0412 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM35950583X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM35950583X | ||
| 003 | DE-627 | ||
| 005 | 20231227131406.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/2159-8290.CD-22-0412 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1225.xml |
| 035 | |a (DE-627)NLM35950583X | ||
| 035 | |a (NLM)37449843 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Stossel, Chani |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Spectrum of Response to Platinum and PARP Inhibitors in Germline BRCA-Associated Pancreatic Cancer in the Clinical and Preclinical Setting |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.08.2023 | ||
| 500 | |a Date Revised 13.12.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions | ||
| 520 | |a SIGNIFICANCE: glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 650 | 7 | |a Platinum |2 NLM | |
| 650 | 7 | |a 49DFR088MY |2 NLM | |
| 700 | 1 | |a Raitses-Gurevich, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Atias, Dikla |e verfasserin |4 aut | |
| 700 | 1 | |a Beller, Tamar |e verfasserin |4 aut | |
| 700 | 1 | |a Glick Gorman, Yulia |e verfasserin |4 aut | |
| 700 | 1 | |a Halperin, Sharon |e verfasserin |4 aut | |
| 700 | 1 | |a Peer, Eyal |e verfasserin |4 aut | |
| 700 | 1 | |a Denroche, Robert E |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Amy |e verfasserin |4 aut | |
| 700 | 1 | |a Notta, Faiyaz |e verfasserin |4 aut | |
| 700 | 1 | |a Wilson, Julie M |e verfasserin |4 aut | |
| 700 | 1 | |a O'Kane, Grainne M |e verfasserin |4 aut | |
| 700 | 1 | |a Haimov Talmoud, Elina |e verfasserin |4 aut | |
| 700 | 1 | |a Amison, Nora |e verfasserin |4 aut | |
| 700 | 1 | |a Schvimer, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Salpeter, Seth J |e verfasserin |4 aut | |
| 700 | 1 | |a Bar, Vered |e verfasserin |4 aut | |
| 700 | 1 | |a Zundelevich, Adi |e verfasserin |4 aut | |
| 700 | 1 | |a Tirosh, Itay |e verfasserin |4 aut | |
| 700 | 1 | |a Tal, Rotem |e verfasserin |4 aut | |
| 700 | 1 | |a Dinstag, Gal |e verfasserin |4 aut | |
| 700 | 1 | |a Kinar, Yaron |e verfasserin |4 aut | |
| 700 | 1 | |a Eliezer, Yonatan |e verfasserin |4 aut | |
| 700 | 1 | |a Ben-David, Uri |e verfasserin |4 aut | |
| 700 | 1 | |a Gavert, Nancy S |e verfasserin |4 aut | |
| 700 | 1 | |a Straussman, Ravid |e verfasserin |4 aut | |
| 700 | 1 | |a Gallinger, Steven J |e verfasserin |4 aut | |
| 700 | 1 | |a Berger, Raanan |e verfasserin |4 aut | |
| 700 | 1 | |a Golan, Talia |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cancer discovery |d 2011 |g 13(2023), 8 vom: 04. Aug., Seite 1826-1843 |w (DE-627)NLM215937023 |x 2159-8290 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2023 |g number:8 |g day:04 |g month:08 |g pages:1826-1843 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/2159-8290.CD-22-0412 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2023 |e 8 |b 04 |c 08 |h 1826-1843 | ||