Cetuximab treatment for metastatic colorectal cancer with KRAS p.G13D mutations improves progression-free survival

Osumi, Hiroki; Shinozaki, Eiji; Osako, Masahiko; Kawazoe, Yoshimasa; Oba, Masaru; Misaka, Takaharu; Goto, Takashi; Kamo, Hitomi; Suenaga, Mitsukuni; Kumekawa, Yosuke; Ogura, Mariko; Ozaka, Masato; Matsusaka, Satoshi; Chìn, Keisho; Hatake, Kiyohiko; Mizunuma, Nobuyuki

doi:10.3892/mco.2015.602

Cited by 15 publications

(18 citation statements)

References 10 publications

(10 reference statements)

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“…We tested a series of five shRNA constructs in three gallbladder tumor cell lines expressing ERBB2 with wild type KRAS in OCUG1 cells, along with G415 and NOZ cells harboring the KRAS (G13D) and KRAS (G12V) mutant alleles, respectively. We identified three shRNA constructs that efficiently knocked down expression of ERBB2 and inhibited the constitutive phosphorylation of MAPK in OCUG1 and G415 cells but not in NOZ cells (Figure 2A), consistent with drug sensitive outcome described in colorectal cancer wherein cells harboring wild type KRAS or mutant KRAS (G13D) allele are sensitive to EGFR inhibitor but not those harboring mutant KRAS (G12V) mutant allele (Osumi et al, 2015). This suggests that KRAS (G13D) but not KRAS (G12V) still requires upstream EGFR signaling in gallbladder cancer cells, similar to as established in colorectal cancer (Kumar et al, 2014).…”

Section: Erbb2 and Egfr Are Essential For Gallbladder Cancer Cells Nosupporting

confidence: 76%

ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

Iyer

Shrikhande

Ranjan

et al. 2018

Preprint

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The uncommonness of gallbladder cancer has contributed to the generally poor understanding of the disease, with scant reports restricted to advance-stage tumors. Here, using an integrated analysis of whole exome and phospho-proteome, we show recurrent activating ERBB2 and KRAS somatic mutations are present in 6 and 3 of 44 early-stage rare gallbladder tumors, respectively. In vitro and in vivo cell-based and biochemical assays reveal an essential role of ErbB pathway activation for the survival of gallbladder cells. Interestingly, the genetic and pharmacological dependencies of gallbladder cells are dependent on the KRAS mutant allele status, reminiscent of the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer. In overall, we present the first evidence that the presence of KRAS (G12V), but not KRAS (G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, leading to an early adoption of an approved treatment regimen for gallbladder cancer patients.

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Section: Erbb2 and Egfr Are Essential For Gallbladder Cancer Cells Nosupporting

confidence: 76%

ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

Iyer

Shrikhande

Ranjan

et al. 2018

Preprint

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“…KRAS mutations frequently occur in many types of human cancers, for example in 70–90% of pancreatic cancer, 30–60% of colon cancer and 15–50% of lung cancer patients12. Moreover, activating oncogenic KRAS mutations are often associated with resistance to chemotherapy and targeted therapies in CRC3839. Due to the poor prognosis for cancer patients with mutated KRAS, much effort has been spent on developing specific therapies for targeting oncogenic KRAS.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of the miR-16-KRAS axis promotes colorectal cancer

You

Liang

Sun

et al. 2016

Sci Rep

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KRAS plays a significant role in the etiology and progression of colorectal cancer (CRC), but the mechanism underlying this process has not been fully elucidated. In this study, we found that the KRAS protein levels were higher in CRC tissues than in the normal adjacent tissues, whereas its mRNA levels varied irregularly, suggesting that a post-transcriptional mechanism is involved in the regulation of KRAS. Then, we performed bioinformatic analyses to search for miRNAs that potentially target KRAS. We predicted and experimentally validated that miR-16 directly recognizes the 3′-UTR of the KRAS transcript and regulates KRAS expression. Furthermore, the in vitro results showed that the repression of KRAS by miR-16 suppressed the proliferation and invasion and induced the apoptosis of CRC cells, and the in vivo results revealed that miR-16 exerted a tumor-suppressive effect by negatively regulating KRAS in xenograft mice. Taken together, our findings provide evidence supporting the role of miR-16 as a tumor suppressor in CRC by targeting KRAS.

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“…2a), consistent with drug sensitive outcome described in colorectal cancer wherein cells harboring wild type KRAS or mutant KRAS (G13D) allele are sensitive to EGFR inhibitor but not those harboring mutant KRAS (G12V) mutant allele. 43 This suggests that KRAS (G13D) but not KRAS (G12V) still requires upstream EGFR signaling in gallbladder cancer cells, similar to as established in colorectal cancer. 44 Next, we used these cells to demonstrate that knockdown of ERBB2 inhibited anchorageindependent growth, cell survival, cell invasion and migration efficiently in OCUG1 and G415 cells but not in NOZ cells (Figs.…”

Section: Resultsmentioning

confidence: 76%

“…We identified three shRNA constructs that efficiently knocked down expression of ERBB2 and inhibited the constitutive phosphorylation of MAPK in OCUG1 and G415 cells but not in NOZ cells (Fig. a ), consistent with drug sensitive outcome described in colorectal cancer wherein cells harboring wild type KRAS or mutant KRAS (G13D) allele are sensitive to EGFR inhibitor but not those harboring mutant KRAS (G12V) mutant allele . This suggests that KRAS (G13D) but not KRAS (G12V) still requires upstream EGFR signaling in gallbladder cancer cells, similar to as established in colorectal cancer .…”

Section: Resultsmentioning

confidence: 81%

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer

Iyer

Shrikhande

Ranjan

et al. 2018

Intl Journal of Cancer

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The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n=25) and recurrent mutations in 14% tumors (n=44); along with co-occurring KRAS mutation in 7% tumors (n=44). We demonstrate that ERBB2 heterodimerize with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatninb inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.

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Cetuximab treatment for metastatic colorectal cancer with KRAS p.G13D mutations improves progression-free survival

Cited by 15 publications

References 10 publications

ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer

Deregulation of the miR-16-KRAS axis promotes colorectal cancer

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer

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