KRAS allel-specific activity of sunitinib in an isogenic disease model of colorectal cancer

Abstract

Our isogenic cell culture model suggests that KRAS mutations in SW48 colorectal cancer cells are linked to resistance to the multityrosine kinase inhibitor sunitinib. KRAS G13D mutant SW48 cells represented the KRAS subspecies with the lowest grade of resistance. Future studies will have to clarify whether KRAS can be used to guide sunitinib treatment or-in general-a treatment with a multityrosine kinase inhibitor in mCRC.

KRAS exon 2 mutations influence activity of regorafenib in an SW48-based disease model of colorectal cancer

“…The varying effects of different KRAS mutations, which can render tumor cell proliferation independent of EGFR stimulation and provide autonomous growth signals that are subsequently processed along the MAPK/ERK pathway, have been outlined for such well-known antibodies as cetuximab and panitumumab, whose application has become an important cornerstone of colorectal cancer therapy [7][8][9][10]. KRAS dependent activity in vitro has also been described for sunitinib, a broad spectrum kinase inhibitor that was shown to stunt the growth of colorectal cancer cells as well as thyroid cancer cells [15,21]. Taking these findings into account, it appears reasonable to believe that the efficacy of regorafenib, which is partly based on the inhibition of EGFRrelated structures, could be inf luenced by KRAS mutations in a similar way.…”

“…It is of great interest to note that several retrospective analyses have reported on differences between the seven most frequently tested KRAS mutations located in codons 12 and 13 of exon 2 concerning clinical presentation of patients and functional behavior of tumors [11][12][13][14][15]. In mCRC, as described by various authors, mutations located in codon 13 (G13D) might be associated with some response to cetuximab in pretreated patients and in patients following cetuximab-based first-line regimens.…”

KRAS and HRAS mutations confer resistance to MET targeting in preclinical models of MET‐expressing tumor cells

“…In this respect, studies involving multikinase small molecule inhibitors may serve as good examples. For sunitinib treatment, distinct resistance patterns were reported for different KRAS mutations in SW48 colorectal cancer, with the lowest chemosensitivity seen for the G13D mutation (Modest et al., 2013). A different sensitivity pattern was detected for ERK phosphorylation as well (Modest et al., 2013).…”

“…For sunitinib treatment, distinct resistance patterns were reported for different KRAS mutations in SW48 colorectal cancer, with the lowest chemosensitivity seen for the G13D mutation (Modest et al., 2013). A different sensitivity pattern was detected for ERK phosphorylation as well (Modest et al., 2013). We also observed a broad range of phenotypic divergence between the different mutant cell lines, indicating that it might be important to stratify the clinical response by the type of mutation rather than in a general mutated/non‐mutated manner.…”

KRAS status and resistance to epidermal growth factor receptor tyrosine‐kinase inhibitor treatment in patients with metastatic colorectal cancer: a meta‐analysis

“…It can regulate biological cellular responses such as tumour proliferation, survival and differentiation [24]. Mutations in downstream signalling effectors of EGFR could result in resistance to EGFR inhibitors [25][26][27].…”