Pharmacogenomics-based subtype decoded implications for risk stratification and immunotherapy in pancreatic adenocarcinoma

TL;DR

This study identifies three pharmacogenomics-based subtypes of pancreatic cancer, each with distinct treatment responses and survival outcomes, offering new strategies for personalized therapy.

Contribution

The study introduces a novel pharmacogenomics-based classification of pancreatic adenocarcinoma subtypes with distinct clinical and therapeutic implications.

Findings

Three pharmacogenomics subtypes were identified with distinct prognostic, biological, and immunotherapy profiles.

Subtype 2 showed immunocompetent features and potential for immunotherapy, while Subtype 3 had favorable outcomes and metabolic distinctiveness.

Subtype 1 was associated with poor prognosis, resistance to chemotherapy, and chromosome instability, with ITGB6 knockdown enhancing 5-fluorouracil sensitivity.

Abstract

With fatal malignant peculiarities and poor survival rate, outcomes of pancreatic adenocarcinoma (PAAD) were frustrated by non-response and even resistance to therapy due to heterogeneity across clinical patients. Nevertheless, pharmacogenomics has been developed for individualized-treatment and still maintains obscure in PAAD.

A total of 964 samples from 10 independent multi-center cohorts were enrolled in our study. With drug response data from the profiling of relative inhibition simultaneously in mixtures (PRISM) and genomics of drug sensitivity in cancer (GDSC) databases, we established and validated multidimensionally three pharmacogenomics-classified subtypes using non-negative matrix factorization (NMF) and nearest template prediction (NTP) algorithms, separately. The heterogenous biological characteristics and precision medicine strategies among subtypes were further investigated.

Three pharmacogenomics-classified subtypes after stable and reproducible validation, distinguished in six aspects of prognosis, biological peculiarities, immune landscapes, genomic variations, immunotherapy and individualized management strategies. Subtype 2 was close to immunocompetent phenotype and projected to immunotherapy; Subtype 3 held most favorable outcomes and metabolic pathways distinctively, promising to be treated with first-line agents. Subtype 1 with worst prognosis, was anticipated to chromosome instability (CIN) phenotype and resistant to chemotherapeutic agents. In addition, ITGB6 contributed to subtype 1 resistance to 5-fluorouracil, and knockdown of ITGB6 enhanced sensitivity to 5-fluorouracil in in vitro experiments. Ultimately, appropriate clinical stratified treatments were assigned to corresponding subtypes according to pharmacogenomic transcripts. Some limitations were not taken into account, thus needs to be supported by more research.

A span-new molecular subtype exploited for PAAD uncovered an insight into precise medication on ground of pharmacogenomics, and highly refined multiple clinical management strategies for specific patients.

The online version contains supplementary material available at 10.1186/s10020-024-01049-6.

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