Phase II Open-Label Study to Assess Efficacy and Safety of Lenalidomide in Combination with Cetuximab in KRAS-Mutant Metastatic Colorectal Cancer

Siena, Salvatore; Cutsem, Éric Van; Li, Mingyu; Jungnelius, Ulf; Romano, Andrea; Beck, Robert; Bencardino, Katia; Elez, Maria Elena; Prenen, Hans; Sanchis, Mireia; Tejpar, Sabine; Gandhi, Anita K.; Shi, Tao; Tabernero, Josep

doi:10.1371/journal.pone.0062264

Cited by 20 publications

(13 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…stimulation. Lenalidomide has been tested in phase I and phase II clinical trials for sporadic CRCs but clinical response has been poor (40). Often these trials are in advanced metastatic tumours which contain multiple oncogenic driver mutations and aberrant signalling pathways.…”

Section: Discussionmentioning

confidence: 99%

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

Sapkota

Dunbar

Macartney

2020

Preprint

View full text Add to dashboard Cite

Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling neo-substrate recruitment and degradation via the ubiquitin-proteasome system. Here, we report FAM83F as such a neo-substrate. We recently showed that the eight FAM83 proteins (A-H) interact with members of the serine/threonine protein kinase CK1 family, to regulate their subcellular distribution and distinct biological roles. CK1α is a well-established IMiD neo-substrate and we demonstrate here that IMiD-induced FAM83F degradation requires its association with CK1α. Despite all FAM83 proteins interacting with CK1α, no other FAM83 protein is degraded by IMiDs. FAM83F is localised to the plasma membrane, and consistent with this, IMiD treatment results in depletion of both FAM83F and CK1α levels from the plasma membrane. We have recently identified FAM83F as a mediator of the canonical Wnt signalling pathway. The IMiD-induced degradation of FAM83F attenuated Wnt signalling in colorectal cancer cells and removed CK1α from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. Intriguingly, in many cancer cell lines, IMiD-induced degradation of CK1α is only modest and incomplete. In line with this observation, the expression of FAM83G, which also binds to CK1α, appears to attenuate the IMiD-induced degradation of CK1α, suggesting a protective role for FAM83G on CK1α. Our findings reveal that the efficiency of target protein degradation by IMiDs, and perhaps other degraders such as PROTACs, relies on the nature of the inherent multiprotein complex in which the target protein exists. Our findings unearth opportunities for developing degraders to target specific protein complexes.

show abstract

Section: Discussionmentioning

confidence: 99%

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

Sapkota

Dunbar

Macartney

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…A clinical trial by Siena et al [28] showed the efficacy and safety of a combination treatment with lenalidomide and cetuximab in KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog)-mutant metastatic colorectal cancer patients and implicated lenalidomide as an activator of T cells, which may play a role in its antitumor activity. Additionally, the down-regulation of B cell counts by lenalidomide may be linked to its activity in B cell malignancies.…”

Section: Discussionmentioning

confidence: 99%

Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model

Nguyen-Pham

Lee

et al. 2017

Oncotarget

View full text Add to dashboard Cite

In this study, we investigated efficacy of lenalidomide in combination with tumor antigen-loaded dendritic cells (DCs) in murine colon cancer model. MC-38 cell lines were injected subcutaneously to establish colon cancer-bearing mice. After tumor growth, lenalidomide (50 mg/kg/day) was injected intraperitoneally on 3 consecutive days in combination with tumor antigen-loaded DC vaccination on days 8, 12, 16, and 20. The tumor antigen-loaded DCs plus lenalidomide combination treatment exhibited a significant inhibition of tumor growth compared with the other groups. These effects were associated with a reduction in immune suppressor cells, such as myeloid-derived suppressor cells and regulatory T cells, with the induction of immune effector cells, such as natural killer cells, CD4+ T cells and CD8+ T cells in spleen, and with the activation of cytotoxic T lymphocytes and NK cells. This study suggests that a combination of tumor antigen-loaded DC vaccination and lenalidomide synergistically enhanced antitumor immune response in the murine colon cancer model, by inhibiting the generation of immune suppressive cells and recovery of effector cells, and demonstrated superior polarization of Th1/Th2 balance in favor of Th1 immune response. This combination approach with DCs and lenalidomide may provide a new therapeutic option to improve the treatment of colon cancer.

show abstract

“…In contrast, our own search yielded a total of 6777 records of which 45 [3][4][5] were RCTs. Of the 37 [3][4][5][6][7][8][9][10][11][12][13][14][15][16]19,20,[22][23][24][25][26][27][28][30][31][32][33][34][36][37][38]40,41,43,45,47,48 trials of cetuximab, 32 [3][4][5][6][8][9][10][11][12][14][15][16]…”

Section: Search Strategy and Missing Trialsmentioning

confidence: 99%

Letter to the editor

Sterrantino

Miroddi

Phillips

et al. 2016

Intl Journal of Cancer

View full text Add to dashboard Cite

Dear Editor, We are writing to bring serious concerns about the validity of the article "Hematologic toxicity assessment in solid tumor patients treated with cetuximab: A pooled analysis of 18 randomized controlled trials" 1 authored by Ran Cui et al. and recently published by the International Journal of Cancer to your attention. After careful reading, we firmly believe that the review uses inappropriate methods and incorrect data, and therefore that the conclusions are misleading.We should be clear that the reason that we have been able to consider the data so carefully is that our group is conducting a systematic review on serious thromboembolic adverse events which has a very similar design (PROSPERO registration number CRD42014009165 2 ), although our systematic review also includes randomized controlled trials (RCTs), in which panitumumab (another approved anti-EGFR monoclonal antibody) is tested as an add-on to standard regimens.We detail the many shortcomings of the research reported by Cui et al. below. Search Strategy and Missing TrialsWe were surprised by the small number of records (511) returned by the authors' initial search, the number of RCTS identified (18) and by the small number of articles that were excluded on grounds of lack of data (2). In contrast, our own search yielded a total of 6777 records of which 45 3-5,7-48 were RCTs. Of the 37 [3][4][5][6][7][8][9][10][11][12][13][14][15][16]19,20,[22][23][24][25][26][27][28][30][31][32][33][34][36][37][38]40,41,43,45,47,48 trials of cetuximab, 32 [3][4][5][6][8][9][10][11][12][14][15][16]19,20,[22][23][24][25][26][27][28][30][31][32][33][34][36][37][38]40,41,43,45,47,48 reported data on hematologic toxicities.Cui et al. do not report their search strategies in full, making it difficult to have confidence in their quality. From the information given, it would seem that although there are several rigorous search filters that can be used to identify RCTs, none of these were used in either MEDLINE or Embase. It also seems that the Cochrane Central Register of Controlled Trials was not used. The impact of these choices would be to restrict the number of articles identified by the literature searching.As of October 31, 2013, the time at which the literature search by Cui et al. was done, 6 of the additional 16 RCTs that we identified were already published. These 6 trials (including over 1,700 participants) should therefore have been identified and added to the 18 trials that they included (Table 1).To date, further data from >5,000 patients are available, as compared to the analysis of Cui et al.; around one-third of these data were already published at the time of their search, and therefore have been missed from the review.

show abstract

Phase II Open-Label Study to Assess Efficacy and Safety of Lenalidomide in Combination with Cetuximab in KRAS-Mutant Metastatic Colorectal Cancer

Cited by 20 publications

References 34 publications

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

Combination therapy with dendritic cells and lenalidomide is an effective approach to enhance antitumor immunity in a mouse colon cancer model

Letter to the editor

Contact Info

Product

Resources

About