Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer

Alshammari, Kanan; Aung, Kyaw Lwin; Zhang, Tong; Razak, Albiruni R. Abdul; Serra, Stefano; Stockley, Tracy; Wang, Lisa; Nguyen, Jessica; Spreafico, Anna; Hansen, Aaron Richard; Zwir, D.; Siu, Lillian L.; Bédard, Philippe L.

doi:10.1016/j.clcc.2021.07.004

Cited by 10 publications

(6 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…37 Although its expression is significantly lower in CRC than in normal colorectal tissue, 24,38 LRIG1 expression is not a prognostic biomarker in CRC at the protein and mRNA levels. 38,39 WT patients 41 and targeting EGFR and BRAF in BRAF-mutant patients. 42 Inhibition of BMP could be an option for indirectly suppressing EGFR in combination with MEK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, targeting the EGFR/RAS/RAF/MEK pathway is a major strategy for the treatment of advanced CRC. Recently, combination therapies targeting more than one molecule in the same pathway have been used in clinical trials, such as targeting EGFR and MEK in KRAS WT patients 41 and targeting EGFR and BRAF in BRAF‐mutant patients. 42 Inhibition of BMP could be an option for indirectly suppressing EGFR in combination with MEK inhibitors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK‐dependent colorectal cancer

et al. 2023

View full text Add to dashboard Cite

The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context‐dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP‐rich environment based on curation of two publicly available RNA‐sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine‐rich repeats and immunoglobulin‐like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth‐suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA‐approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient‐derived organoids could offer functional biomarkers for predicting potential responders to this regimen.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK‐dependent colorectal cancer

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Prior studies of combined EGFR and MEK inhibition with panitumumab + trametinib, respectively, suggest that this regimen is highly toxic, with toxicities being primarily dermatologic in nature (dermatitis acneiform). 20 , 21 Current trials evaluating MEK inhibitors with broader inhibitors of upstream signaling, including drugs targeting SHP2 and SOS, are ongoing and will determine the safety and efficacy of these combinations.…”

Section: Discussionmentioning

confidence: 99%

Phase Ib/II Study of the Efficacy and Safety of Binimetinib (MEK162) Plus Panitumumab for Mutant or Wild-Type RAS Metastatic Colorectal Cancer

Van Cutsem,

Yaeger,

Delord

et al. 2023

The Oncologist

View full text Add to dashboard Cite

Introduction Activating RAS gene mutations occur in approximately 55% of patients with metastatic colorectal cancer (mCRC) and are associated with poorer clinical outcomes due to epidermal growth factor receptor (EGFR) blockade resistance. Combined EGFR and mitogen-activated protein kinase (MEK) inhibition may extend response to EGFR inhibition and overcome acquired resistance. This phase Ib/II dose escalation trial evaluated the safety and activity of dual inhibition with binimetinib (MEK1/2 inhibitor) and panitumumab (EGFR inhibitor [EGFRi]) in patients with RAS mutant or BRAF wild type (WT)/RAS WT mCRC. Methods Phase Ib dose escalation started with binimetinib 45 mg twice daily plus panitumumab 6 mg/kg administered every 2 weeks. In the phase II study, patients with measurable mCRC were enrolled into 4 groups based on previous anti-EGFR monoclonal antibody therapy and RAS mutational status. Results No patients in the phase Ib portion (n = 10) had a response; 70% of patients had stable disease. In the phase II portion (n = 43), overall response rate (ORR, confirmed) was 2.3% with one partial response in the RAS WT group, DCR was 30.2%, and median progression-free survival was 1.8 months (95%CI, 1.6-3.3). All patients experienced ≥1 adverse event, with the most common being diarrhea (71.7%), vomiting (52.8%), nausea (50.9%), fatigue (49.1%), dermatitis acneiform (43.4%), and rash (41.5%). Most patients required treatment interruption or dose reduction due to difficulties tolerating treatment. Conclusions The combination of binimetinib and panitumumab had substantial toxicity and limited clinical activity for patients with mutant or WT RAS mCRC, independent of EGFRi treatment history (Trial registration: NCT01927341).

show abstract

“…Elevated expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 was consistent with their role in drug resistance of colorectal carcinoma and correlation with a poor prognosis for patients [ 31 , 37 , 38 ]. Selecting trametinib to model drug resistance was based on its specificity and potency and use in clinical trials of colorectal cancer [ 39 , 40 ]. Our finding is consistent with studies that showed cyclic treatments of tumor xenografts with MEK inhibitors did not reduce tumor size [ 21 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells

Lamichhane,

Luker,

Agarwal

et al. 2023

Oncotarget

View full text Add to dashboard Cite

Drug resistance is a major barrier against successful treatments of cancer patients. Gain of stemness under drug pressure is a major mechanism that renders treatments ineffective. Identifying approaches to target cancer stem cells (CSCs) is expected to improve treatment outcomes for patients. To elucidate the role of cancer stemness in resistance of colorectal cancer cells to targeted therapies, we developed spheroid cultures of patient-derived BRAF mut and KRAS mut tumor cells and studied resistance mechanisms to inhibition of MAPK pathway through phenotypic and gene and protein expression analysis. We found that treatments enriched the expression of CSC markers CD166, ALDH1A3, CD133, and LGR5 and activated PI3K/Akt pathway in cancer cells. We examined various combination treatments to block these activities and found that a triple combination against BRAF, EGFR, and MEK significantly reduced stemness and activities of oncogenic signaling pathways. This study demonstrates the feasibility of blocking stemness-mediated drug resistance and tumorigenic activities in colorectal cancer.

show abstract

Phase II Trial of Trametinib and Panitumumab in RAS/RAF Wild Type Metastatic Colorectal Cancer

Cited by 10 publications

References 34 publications

Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK‐dependent colorectal cancer

Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK‐dependent colorectal cancer

Phase Ib/II Study of the Efficacy and Safety of Binimetinib (MEK162) Plus Panitumumab for Mutant or Wild-Type RAS Metastatic Colorectal Cancer

Inhibiting BRAF/EGFR/MEK suppresses cancer stemness and drug resistance of primary colorectal cancer cells

Contact Info

Product

Resources

About