Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6

Ziemke, Elizabeth K.; Dosch, Joseph S.; Maust, Joel D.; Shettigar, Amrith; Sen, Ananda; Welling, Theodore H.; Hardiman, Karin M.; Sebolt–Leopold, Judith S.

doi:10.1158/1078-0432.ccr-15-0829

Cited by 77 publications

(58 citation statements)

References 27 publications

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“…Given these concerns, our data demonstrated preclinical efficacy of combination MEK and CDK4/6 inhibitors in RAS-mutant CRCs. This data also complements the recent report of the combination of palbociclib and trametinib in KRAS -mutant CRC PDX models [63], but demonstrates that inhibition of phospho-S6 is a potential pharmacodynamic biomarker, and uniquely demonstrates that this inhibition is synergistic with the combination of CDK4/6 and MEK inhibitors in a broader number and mutational diversity of cell lines, including “atypical” KRAS A146T mutant CRC PDX models. Our data has justified development of a planned phase II clinical trial of the combination in patients with refractory metastatic RAS-mutant CRC.…”

Section: Discussionsupporting

confidence: 86%

Efficacy of the combination of MEK and CDK4/6 inhibitorsin vitroandin vivoin KRAS mutant colorectal cancer models

et al. 2016

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PurposeThough the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo.ResultsThe combination of MEK and CDK4/6 inhibitors synergistically inhibited cancer cell growth in vitro and caused tumor regression in vivo in cell line and patient-derived xenograft models. Combination therapy markedly decreased levels of phosphorylated ribosomal protein S6 both in vitro and in vivo and decreased Ki67 staining in vivo.Experimental DesignWe performed in vitro proliferation, colony formation, apoptosis, and senescence assays, and Western blots, on a panel of 11 KRAS mutant CRC cell lines treated with the MEK inhibitor MEK162, the CDK4/6 inhibitor palbociclib, or the combination. We also treated 4 KRAS mutant CRC cell line and patient-derived xenografts with the MEK inhibitor trametinib, the CDK4/6 inhibitor palbociclib, or the combination, and performed immunohistochemical and reverse phase protein array analysis.ConclusionsCombined inhibition of both MEK and CDK4/6 is effective in preclinical models of KRAS mutant CRC and justifies a planned phase II clinical trial in patients with refractory KRAS-mutant CRC.Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.

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Section: Discussionsupporting

confidence: 86%

Efficacy of the combination of MEK and CDK4/6 inhibitorsin vitroandin vivoin KRAS mutant colorectal cancer models

et al. 2016

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“…However, many genes in these regions are not eligible as candidate genes with major roles in colorectal carcinogenesis. Of the many candidate genes, we identified cyclin‐dependent kinase (CDK) 4/6 on 12q14.1–14.2,32, 33 death‐associated protein kinase 1 (DAPK1) on 9q21–22,34 retinoic acid receptor ( RAR ) β 235 and topoisomerase II beta (TOP2B) on 3p2436 as representative genes contributing to tumor development. Of these candidate genes, we selected CDK4/6 and RARβ2 as genes involved in colorectal tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

Takahashi

Sugai

Habano

et al. 2016

Intl Journal of Cancer

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Differences in the pathogenesis of microsatellite stable (MSS) sporadic colorectal cancers (CRCs) between left‐sided CRC (LC) and right‐sided CRC (RC) have not been clarified. To identify pathogenesis‐related genomic differences between MSS CRCs within the two locations, we performed a comprehensive molecular analysis using crypt isolation with samples from 92 sporadic CRCs. Microsatellite instability (MSI; high and low/negative) and DNA methylation status (low methylation epigenome; intermediate methylation epigenome [IME] or high methylation epigenome [HME]) were determined using polymerase chain reaction (PCR) microsatellite analysis and PCR‐bisulfite pyrosequencing, respectively. Additionally, mutations in the TP53, KRAS, BRAF and PIK3CA genes were examined using PCR‐bisulfite pyrosequencing (for KRAS and BRAF mutations) or PCR‐single conformation polymorphism (for TP53 and PIK3CA mutations), followed by sequencing of aberrant bands. Finally, a genome‐wide study using a copy number alteration (CNA)‐targeted single nucleotide polymorphism array was performed. Ninety‐two CRCs were classified into 71 MSS and 21 MSI phenotypes. We examined 71 CRCs with the MSS phenotype (LC, 56; RC, 15). Mutations in KRAS were associated with RC with the MSS phenotype, whereas mutations in TP53 were more frequently found in LC with the MSS phenotype. There were significant differences in the frequencies of KRAS and TP53 mutations in the IME between LC and RC with the MSS phenotype. Although CNA gains were associated with LC with the MSS phenotype, CNA losses were not major alterations associated with the MSS phenotype. These findings suggested that the molecular pathogenesis of the MSS phenotype in LC was different from that in RC.

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“…[5][6][7][8][9][10][11] We analyzed the combinatorial effects of palbociclib with the commonly used chemotherapy agents against CRC, as a prelude to possible translation. Chou-Talalay analysis revealed that palbociclib can synergize with a variety of chemotherapies under hypoxia (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…8 Synergy of palbociclib with a MEK inhibitor has also been demonstrated in KRAS mutant colon cancer in vivo. 9,10 Vemurafenib-resistant tumors remain sensitive to palbociclib suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an approach to overcome recurrence of vemurafenibresistant, metastatic tumors. 11 In brief, these studies indicate combinatorial administration of a CDK4/6 inhibitor with other chemo-or targeted-therapies could provide a promising treatment against various malignancies.…”

Section: Introductionmentioning

confidence: 99%

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

et al. 2017

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Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1a regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3b. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1a accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3b signaling and GSK-3b expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1a accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.

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Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6

Cited by 77 publications

References 27 publications

Efficacy of the combination of MEK and CDK4/6 inhibitorsin vitroandin vivoin KRAS mutant colorectal cancer models

Efficacy of the combination of MEK and CDK4/6 inhibitorsin vitroandin vivoin KRAS mutant colorectal cancer models

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

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