Resistance Mechanism in Precision Medicine in PDAC

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Talia Golan, Sheba Medical Center

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Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations (92%) and alterations in DNA damage repair (DDR) pathways, including BRCA1/2 mutations. While PARP inhibitors (PARPi) show efficacy in BRCA-mutant PDAC, resistance mechanisms limit their effectiveness.

 

Methods: We analyzed clinical outcomes of 125 patients with germline BRCA-mutant PDAC, generating patient-derived xenografts (PDX) from 30 patients at various treatment timepoints. Response patterns were evaluated using in vivo and ex vivo culture (EVOC) models. Additionally, we investigated the interaction between KRAS signaling and DDR pathways. Furthermore, PDX models were also generated from patients with differing KRAS mutations ( BRCA WT, N=120).

 

Results: Patients demonstrated three distinct response patterns to platinum/PARPi therapy: refractory (OS <6 months), acquired resistance (OS <36 months), and long-term response (OS >36 months). PDX and EVOC models accurately predicted clinical responses. Primary resistance mechanisms included restoration of homologous recombination proficiency and KRAS amplification. Preliminary preclinical data from our lab demonstrates efficacy of KRASi combined with PARP inhibitor on patients-derived models, from BRCA wt and BRCAmut PDAC.

A patient receiving third-line therapy with KRASi demonstrated a prolonged PFS. At disease progression, a liquid biopsy revealed a de novo alteration in the ATM gene, suggesting that resistance to KRASi may be developed through the DDR pathway. This case underscores the potential role of DDR-related alterations, as mechanisms of therapeutic resistance.

 

Conclusions: The combination of KRASi and PARPi represents a promising therapeutic strategy for PDAC, potentially benefiting patients regardless of BRCA status. Further investigation of resistance mechanisms and optimal combination strategies is warranted to maximize therapeutic efficacy.

Keywords: Pancreatic cancer, KRAS, PARP inhibitors, DNA damage repair, drug resistance