Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss

Erasimus, Hélène; Kolnik, Vanessa; Lacroix, Frédéric; Sidhu, Sukhvinder; D'Agostino, Stéphane; Lemaitre, Olivier; Rohaut, Alexandre; Sanchez, Isabelle; Thill, Gilbert; Didier, Michel; Debussche, Laurent; Marcireau, Christophe

doi:10.1158/2767-9764.crc-22-0301

Cited by 2 publications

(1 citation statement)

References 52 publications

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“…SMAD4, a transforming growth factor (TGF)-β/BMP signaling effector and a tumor suppressor, is frequently mutated in PDAC and actively participates in the interaction between cancer and stromal myeloid cells and mediates the response of cancer cells to stromal chemokine [ 67 ]. It drives distal dissemination and its loss is associated with and poor prognosis in PDAC [ 68 – 70 ]. ARID1A-deficient undifferentiated carcinoma exhibited cellular discohesion and rhabdoid morphology [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

Huang,

Lv,

Guan

et al. 2024

J Transl Med

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Aims We previously showed that the nab-paclitaxel plus S-1 (NPS) regimen had promising effects against metastatic pancreatic ducal adenocarcinoma (mPDAC), whose efficacy however could not be precisely predicted by routine biomarkers. This prospective study aimed to investigate the values of mutations in circulating tumor DNA (ctDNA) and their dynamic changes in predicting response of mPDAC to NPS chemotherapy. Methods Paired tumor tissue and blood samples were prospectively collected from patients with mPDAC receiving first-line NPS chemotherapy, and underwent next-generation sequencing with genomic profiling of 425 genes for ctDNA. High mutation allelic frequency (MAF) was defined as ≥ 30% and ≥ 5% in tumor tissue and blood, respectively. Kappa statistics were used to assess agreement between mutant genes in tumor and ctDNA. Associations of mutations in ctDNA and their dynamic changes with tumor response, overall survival (OS), and progression-free survival (PFS) were assessed using the Kaplan–Meier method, multivariable-adjusted Cox proportional hazards regression, and longitudinal data analysis. Results 147 blood samples and 43 paired tumor specimens from 43 patients with mPDAC were sequenced. The most common driver genes with high MAF were KRAS (tumor, 35%; ctDNA, 37%) and TP53 (tumor, 37%; ctDNA, 33%). Mutation rates of KRAS and TP53 in ctDNA were significantly higher in patients with liver metastasis, with baseline CA19-9 ≥ 2000 U/mL, and/or without an early CA19-9 response. κ values for the 5 most commonly mutated genes between tumor and ctDNA ranged from 0.48 to 0.76. MAFs of the genes mostly decreased sequentially during subsequent measurements, which significantly correlated with objective response, with an increase indicating cancer progression. High mutations of KRAS and ARID1A in both tumor and ctDNA, and of TP53, CDKN2A, and SMAD4 in ctDNA but not in tumor were significantly associated with shorter survival. When predicting 6-month OS, AUCs for the 5 most commonly mutated genes in ctDNA ranged from 0.59 to 0.84, larger than for genes in tumor (0.56 to 0.71) and for clinicopathologic characteristics (0.51 to 0.68). Repeated measurements of mutations in ctDNA significantly differentiated survival and tumor response. Among the 31 patients with ≥ 2 ctDNA tests, longitudinal analysis of changes in gene MAF showed that ctDNA progression was 60 and 58 days ahead of radiologic and CA19-9 progression for 48% and 42% of the patients, respectively. Conclusions High mutations of multiple driving genes in ctDNA and their dynamic changes could effectively predict response of mPDAC to NPS chemotherapy, with promising reliable predictive performance superior to routine clinicopathologic parameters. Inspiringly, longitudinal ctDNA tracking could predict disease progression about 2 months ahead of radiologic or CA19-9 evaluations, with the potential to precisely devise individualized therapeutic strategies for mPDAC.

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Section: Discussionmentioning

confidence: 99%

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

Huang,

Lv,

Guan

et al. 2024

J Transl Med

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Exploring the molecular mechanisms and therapeutic potential of SMAD4 in colorectal cancer

Shan,

Tian,

Zhang

et al. 2024

Cancer Biology & Therapy

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Colorectal Cancer (CRC) is the third most common cancer worldwide, and the occurrence and development of CRC are influenced by the molecular biology characteristics of CRC, especially alterations in key signaling pathways. The transforming growth factor-β (TGF-β) plays a crucial role in cellular growth, differentiation, migration, and apoptosis, with SMAD4 protein serving as a key transcription factor in the TGF-β signaling pathway, thus playing a significant role in the onset and progression of CRC. CRC is one of the malignancies with a high mortality rate worldwide. Despite significant research progress in recent years, especially regarding the role of SMAD4, its dual role in the early and late stages of tumor progression has promoted further discussion on its complexity as a therapeutic target, highlighting the urgent need for a deeper analysis of its role in CRC. This review aims to explore the function of SMAD4 protein in CRC and its potential as a therapeutic target.

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Genome-wide CRISPR Screen Reveals RAB10 as a Synthetic Lethal Gene in Colorectal and Pancreatic Cancers Carrying SMAD4 Loss

Cited by 2 publications

References 52 publications

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

High somatic mutations in circulating tumor DNA predict response of metastatic pancreatic ductal adenocarcinoma to first-line nab-paclitaxel plus S-1: prospective study

Exploring the molecular mechanisms and therapeutic potential of SMAD4 in colorectal cancer

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