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Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers
Ist Teil von
Science (American Association for the Advancement of Science), 2024-06, Vol.384 (6700), p.eadk0775-eadk0775
Ort / Verlag
Washington: The American Association for the Advancement of Science
Erscheinungsjahr
2024
Link zum Volltext
Quelle
American Association for the Advancement of Science
Beschreibungen/Notizen
How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal–regulated kinase (ERK)–dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.
Editor’s summary Mutations in the KRAS gene are one of the most frequent oncogenic events in human cancer. Drugs that inhibit KRAS have recently been approved for the treatment of KRAS-mutant tumors, but their clinical efficacy is limited by primary innate mechanisms and by treatment-associated resistance. To better understand how KRAS-driven tumors grow and resist therapy, J. A. Klomp et al . established a KRAS-regulated gene transcriptome in KRAS-mutant pancreatic cancer. The KRAS mutant transcriptome was found to be regulated largely through activation of the ERK mitogen-activated protein kinase cascade. In a separate study, J. E. Klomp et al . compiled a comprehensive molecular portrait of aberrant ERK signaling in KRAS-mutated pancreatic cancer and identified more than 1500 ERK substrates. These studies advance our understanding of how ERK supports KRAS-dependent cancer growth and may inform next-generation therapies using KRAS and ERK inhibitors. —Priscilla N. Kelly
INTRODUCTION Recent US Food and Drug Administration approval of direct inhibitors of G12C (Gly 12 →Cys) mutations in the formerly “undruggable” KRAS marks an important milestone in cancer drug discovery, and inhibitors of more prevalent KRAS mutations [G12D/V (Gly 12 →Asp or Val), and others] are now in clinical evaluation. However, notably few patients respond initially, and most of those individuals relapse quickly. Defining genetic markers and drivers of primary and treatment-associated acquired resistance to KRAS inhibitors will be essential to achieve broader and more durable responses. RATIONALE A major molecular output of aberrant KRAS activation involves systemwide deregulation of gene transcription. Despite numerous efforts to establish KRAS-associated gene transcription signatures, present signatures show notably limited overlap, likely reflecting divergent experimental strategies and cancer models. In this work, we sought to define a comprehensive KRAS-dependent transcriptional signature that detects target inhibition in KRAS-mutant cancer patients treated with KRAS mutation–selective inhibitors. RESULTS Most of the previous KRAS signatures, including the present gold-standard Hallmark KRAS signaling gene sets, profiled gene expression changes caused by persistent steady-state expression of mutant KRAS. Instead, we applied RNA sequencing (RNA-seq) to determine transcriptional changes caused by acute KRAS suppression in endogenously KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell lines, thereby limiting the confounding effects of compensation for the loss of KRAS signaling. In contrast to the Hallmark, our KRAS gene signature was strongly enriched in changes in response to pharmacologic inhibition of mutant KRAS in KRAS-mutant PDAC cell lines and tumors, as well as in lung and colorectal xenograft tumors. Thus, the KRAS-regulated transcriptome may be broadly applicable. Despite the plethora of validated and putative KRAS effectors, we found that RAF-MEK-ERK mitogen-activated protein kinase (MAPK) effector signaling alone, but not the PI3K-AKT-mTORC1 pathway, showed that sufficient to support mutant KRAS-dependent PDAC growth. Consistent with this, the KRAS-regulated transcriptome was driven largely through ERK MAPK activity. Pathway analyses showed that our merged KRAS- and ERK-dependent gene signature composed of 278 up-regulated genes was highly enriched in cell cycle processes. A comparison of the ERK-regulated transcriptome and total proteome showed that ~80% of the regulation of protein expression changes was at the level of gene transcription. Another subset was at the level of posttranscriptional mechanisms, including ERK phosphorylation and modulation of the anaphase promoting complex/cyclosome (APC/C), which is involved in cell cycle regulation. Finally, our KRAS-ERK gene signature accurately detected KRAS-ERK target inhibition, and that inhibition correlated generally with clinical responses in KRAS-mutant cancer patients treated with KRAS or ERK inhibitors. An accurate portrait of the molecular output that mirrors aberrant KRAS signaling in cancer patients will further elucidate mechanistically how KRAS drives cancer. CONCLUSION Our study established a KRAS-ERK regulated gene signature that detected KRAS-ERK inhibition in KRAS-mutant cancer patients. Coupled with our ERK-dependent total proteome and phosphoproteome signatures, it revealed that aberrant KRAS signaling drives cancer growth through the regulation of cell cycle progression at multiple levels. The KRAS-ERK transcriptome may define molecular markers for primary and acquired resistance in patients treated with KRAS-ERK MAPK–targeted therapies. KRAS causes ERK-dependent systemwide deregulation of gene transcription. The ERK MAPK effector signaling network regulates the activity of the APC/C cell cycle regulatory complex and a diverse spectrum of functionally distinct proteins that include transcription factor (TF) oncoproteins [e.g., MYC and FRA1 ( FOSL1 )]. ERK-regulated genes encode additional TFs and epigenetic regulators (ER) that modify both histones and DNA, and encode protein kinases (PK) and phosphatases (PP), to regulate secondary changes in gene transcription and protein phosphorylation. E2F, E2 promoter binding factor; G12C/D, Gly 12 →Cys or Asp; KRASi, KRAS inhibitor; NS, nonspecific; siRNA, small interfering RNA; SRF, serum response factor; X, other substrates. [Figure partially created with BioRender.com ]