Integrated analysis of KRAS mutations and MTAP loss in pancreatic cancer reveals potential for combined blockade of KRAS and PRMT5
Authors
Jordi Rodon¹, Daria Yakimova², Andrey Kravets², Ksenia Kudriavtseva², Dmitrii Belousov², Kirill Shaposhnikov², Camila Braganca Xavier¹, Dan Zhao¹, Subham Pant¹, Aleksander Bagaev², David Hong¹, Nikita Kotlov²
- The University of Texas, MD Anderson Cancer Center, Houston. TX, USA
- BostonGene Corporation, Waltham, MA USA
Abstract
Pancreatic adenocarcinoma (PAAD) is one of the most lethal cancers, with a persistently low five-year survival rate. KRAS mutations occur in up to 90% of cases, while MTAP loss, found in 20–30%, has emerged as a promising biomarker for PRMT5 inhibition therapy. With the advent of new KRAS and PRMT5 inhibitors, it is clinically important to study their combined use in PAAD.
WES and RNA-seq data from 437 public PAAD samples and 119 internal TumorPortrait™ cases (2022–2024) were analyzed using BostonGene’s automated pipelines. After filtering for tumor purity >20%, 454 samples remained. MTAP loss was defined as full gene deletion (≥2-copy loss) via Sequenza. Moffitt and tumor microenvironment (TME) transcriptomic subtypes were assigned as previously described (PMID: 38280684). Log-rank and Chi-square tests were used to assess survival and categorical associations, respectively.
Across the cohort, 24% of tumors had MTAP loss and 79.5% had KRAS mutations (m). Specifically, 60.6% were KRASm/MTAP wild-type (WT), 15.4% KRAS-WT/MTAP-WT, 18.9% KRASm/MTAP-loss, and 5.1% KRAS-WT/MTAP-loss. KRAS variants among KRASm/MTAP-loss tumors included G12D (39.5%), G12V (27.9%), G12R (23.3%), and others (9.3%), with no significant difference in distribution compared to KRASm/MTAP-WT tumors (p=0.8). MTAP loss was more frequent in Basal-like than Classical Moffitt subtypes (29.2% vs. 20.7%; p=0.05) and was enriched in Fibrotic TME subtype (p=0.04). It was not associated with disease stage but tended to increase in high-grade tumors (p=0.17). Crucially, MTAP loss was consistently associated with worse survival (p<0.01) in patients treated primarily with systematic chemotherapy, irrespective of KRAS status, Moffitt, or TME subtypes.
While a similar RAS mutation spectrum in MTAP-WT and MTAP-loss tumors suggests similar responsiveness to pan-RAS inhibitors, combining RAS mutation profile with MTAP status may enhance treatment options. Combining pan-RAS and PRMT5 inhibitors may benefit PAAD patients with both KRAS mutations and MTAP-loss. Moreover, the association between MTAP loss and fibrotic TME may support treatment strategies combining PRMT5 inhibitors with immune checkpoint blockade.
WES and RNA-seq data from 437 public PAAD samples and 119 internal TumorPortrait™ cases (2022–2024) were analyzed using BostonGene’s automated pipelines. After filtering for tumor purity >20%, 454 samples remained. MTAP loss was defined as full gene deletion (≥2-copy loss) via Sequenza. Moffitt and tumor microenvironment (TME) transcriptomic subtypes were assigned as previously described (PMID: 38280684). Log-rank and Chi-square tests were used to assess survival and categorical associations, respectively.
Across the cohort, 24% of tumors had MTAP loss and 79.5% had KRAS mutations (m). Specifically, 60.6% were KRASm/MTAP wild-type (WT), 15.4% KRAS-WT/MTAP-WT, 18.9% KRASm/MTAP-loss, and 5.1% KRAS-WT/MTAP-loss. KRAS variants among KRASm/MTAP-loss tumors included G12D (39.5%), G12V (27.9%), G12R (23.3%), and others (9.3%), with no significant difference in distribution compared to KRASm/MTAP-WT tumors (p=0.8). MTAP loss was more frequent in Basal-like than Classical Moffitt subtypes (29.2% vs. 20.7%; p=0.05) and was enriched in Fibrotic TME subtype (p=0.04). It was not associated with disease stage but tended to increase in high-grade tumors (p=0.17). Crucially, MTAP loss was consistently associated with worse survival (p<0.01) in patients treated primarily with systematic chemotherapy, irrespective of KRAS status, Moffitt, or TME subtypes.
While a similar RAS mutation spectrum in MTAP-WT and MTAP-loss tumors suggests similar responsiveness to pan-RAS inhibitors, combining RAS mutation profile with MTAP status may enhance treatment options. Combining pan-RAS and PRMT5 inhibitors may benefit PAAD patients with both KRAS mutations and MTAP-loss. Moreover, the association between MTAP loss and fibrotic TME may support treatment strategies combining PRMT5 inhibitors with immune checkpoint blockade.
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