Molecular Profile Detail

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Profile Name SMAD4 mutant
Gene Variant Detail

SMAD4 mutant (unknown)

Relevant Treatment Approaches

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Molecular Profile Indication/Tumor Type Response Type Relevant Treatment Approaches Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMAD4 inact mut pancreatic cancer sensitive Irinotecan Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring inactivated SMAD4 (mutations or deletion) displayed 4.5-fold greater sensitivity to irinotecan in vitro than wild-type (PMID: 22753594). 22753594
SMAD4 dec exp head and neck squamous cell carcinoma resistant Cetuximab Clinical Study - Cohort Actionable In a clinical study, decreased Smad4 expression level correlated with Erbitux (cetuximab) resistance in head and neck squamous cell carcinoma (HNSCC) patients, which is consistent with cell culture studies demonstrating Erbitux (cetuximab) resistance induced by knocking-down of Smad4 expression in HNSCC cell lines (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma decreased response U0126 Preclinical - Cell culture Actionable In a preclinical study, U0126 demonstrated modest inhibition of Mapk activity and transient growth inhibition in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp pancreatic cancer not applicable N/A Clinical Study Prognostic In clinical and meta-analyses, loss of Smad4 expression and SMAD4 inactivating mutations were associated with decreased survival in patients with pancreatic cancer (PMID: 26947875, PMID: 25760429, PMID: 22504380, PMID: 19584151). 22504380 19584151 25760429 26947875
SMAD4 dec exp head and neck squamous cell carcinoma sensitive Cetuximab + U0126 Preclinical - Cell culture Actionable In a preclinical study, addition of U0126 to Erbitux (cetuximab) restored sensitivity to Erbitux (cetuximab) in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma decreased response SP600125 Preclinical - Cell culture Actionable In a preclinical study, SP600125 demonstrated modest inhibition of Jnk activity and transient growth inhibition in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp head and neck squamous cell carcinoma sensitive Cetuximab + SP600125 Preclinical - Cell culture Actionable In a preclinical study, addition of SP600125 to Erbitux (cetuximab) restored sensitivity to Erbitux (cetuximab) in Smad4 knocked-down head and neck squamous cell carcinoma cells in culture (PMID: 28522603). 28522603
SMAD4 dec exp colorectal cancer not applicable N/A Clinical Study Prognostic In clinical and meta-analyses, decreased expression of Smad4 was correlated with poor prognosis in colorectal cancer (PMID: 25749173, PMID: 19478385, PMID: 25681512, PMID: 26861460). 25749173 19478385 26861460 25681512
EML4 - ALK CDKN2A del FGFR1 T141R SMAD4 Q83* pancreatic ductal adenocarcinoma predicted - resistant Crizotinib Case Reports/Case Series Actionable In a clinical case study, a pancreatic ductal adenocarcinoma patient harboring EML4-ALK along with CDKN2A deletion, FGFR1 T141R, SMAD4 Q83*, and a TP53 splice site mutation, experienced disease progression after 2 months of Xalkori (crizotinib) treatment, then received Alecensa (alectinib) and remained on treatment for at least 3 months (PMID: 28476735). 28476735
EML4 - ALK CDKN2A del FGFR1 T141R SMAD4 Q83* pancreatic ductal adenocarcinoma predicted - sensitive Alectinib Case Reports/Case Series Actionable In a clinical case study, a pancreatic ductal adenocarcinoma patient harboring EML4-ALK along with CDKN2A deletion, FGFR1 T141R, SMAD4 Q83*, and a TP53 splice site mutation, experienced disease progression after 2 months of Xalkori (crizotinib) treatment, then received Alecensa (alectinib) and remained on treatment for at least 3 months (PMID: 28476735). 28476735
SMAD4 mutant colorectal cancer no benefit Cetuximab Clinical Study - Cohort Actionable In a clinical study, Chinese metastatic colorectal cancer patients harboring a SMAD4 mutation did not respond to treatment with Erbitux (cetuximab) and showed a shorter progression-free survival compared to patients with wild-type SMAD4 (median: 90 vs 250 days, p=0.0081) (PMID: 29703253). 29703253
SMAD4 mutant stomach cancer not applicable N/A Guideline Risk Factor Germline mutations in SMAD4 or BMPR1A result in juvenile polyposis syndrome, which is associated with increased risk of developing gastric cancer (NCCN.org). detail...
SMAD4 loss pancreatic carcinoma sensitive SD-093 Preclinical Actionable In a preclinical study, SD-093 reduced the migration and invasiveness of pancreatic carcinoma cell lines lacking Smad4 (PMID: 15289325). 15289325
SMAD4 loss pancreatic adenocarcinoma predicted - sensitive Hydroxychloroquine Clinical Study Actionable In a retrospective analysis of 2 clinical trials, addition of Plaquenil (hydroxychloroquine sulfate) to neoadjuvant chemotherapy resulted in a histopathological response of 2A or better in 76% of patients with pancreatic adenocarcinoma harboring SMAD4 loss (n=25), compared to 37% in SMAD4 wild-type group (n=27) (p=0.006) (J Clin Oncol 38, 2020 (suppl 4; abstr 761); NCT01128296, NCT01978184). detail...
SMAD4 del pancreatic cancer sensitive Irinotecan Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring inactivated SMAD4 (mutations or deletion) displayed 4.5-fold greater sensitivity to irinotecan in vitro than wild-type (PMID: 22753594). 22753594
SMAD4 del pancreatic cancer decreased response Gemcitabine Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring SMAD4 homozygous deletions were half as sensitive to gemcitabine in vitro as wild-type cells (PMID: 22753594). 22753594
SMAD4 del pancreatic cancer sensitive Cisplatin Preclinical Actionable In a preclinical study, pancreatic cancer cell lines harboring SMAD4 homozygous deletions were twice as sensitive to cisplatin in vitro as wild-type cells (PMID: 22753594). 22753594
Clinical Trial Phase Therapies Title Recruitment Status