Cell-Free DNA Profiling to Discover Mechanisms of Exceptional Response to Cabozantinib Plus Panitumumab in a Patient With Treatment Refractory Metastatic Colorectal Cancer

Jia, Jingquan; Morse, Michael A.; Nagy, Rebecca J.; Lanman, Richard B.; Strickler, John H.

doi:10.3389/fonc.2018.00305

Cited by 15 publications

(13 citation statements)

References 51 publications

(61 reference statements)

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“…With the aim of getting a better understanding of the mechanisms of resistance to HER2-directed and EGFR-directed therapies, it has been recently reported that increased expression of MUC1 and MET , decreased expression of PTEN , and an activating mutation in PIK3CA is accompanied with HER2 -amplified in mCRC. These findings strongly highlight the molecular heterogeneity of the resistance to anti-EGFR therapy [39,46,49,50,51,52].…”

Section: Acquired Resistance To Anti-egfr Treatment In Crc Patientsmentioning

confidence: 90%

“…All these data support a role for MET in the generation of an acquired resistance to cetuximab in CRC patients. According to this, in vitro studies demonstrated that HGF-mediated Met activation prevented cetuximab-induced apoptosis or cell cycle arrest in CRC cells [39,51,52]. Preclinical and clinical data suggest that patients with amplified MET in tumors benefit from MET-targeted therapy.…”

Section: Acquired Resistance To Anti-egfr Treatment In Crc Patientsmentioning

confidence: 99%

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Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

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: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

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Section: Acquired Resistance To Anti-egfr Treatment In Crc Patientsmentioning

confidence: 90%

Section: Acquired Resistance To Anti-egfr Treatment In Crc Patientsmentioning

confidence: 99%

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

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“…Similarly, a case report of a treatment refractory patient with metastatic colorectal cancer showed that MET amplification was detected in ctDNA using next-generation sequencing, but not in tissue biopsy samples. The significant response that the patient experienced after treatment with the combination of cabozantinib plus panitumumab led to the suggestion that MET amplification in ctDNA may be a predictive biomarker for response [244]. Finally, in NSCLC, a recent study demonstrated the potential clinical utility of ctDNA as a guide for therapy when tissue DNA was insufficient or unavailable [240].…”

Section: Vi-b-circulating Tumor Dnamentioning

confidence: 99%

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

Moosavi

Giovannetti

Saso³

et al. 2019

Critical Reviews in Clinical Laboratory Sciences

125

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Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.

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“…In the past two decades, systemic chemotherapy b one of the foremost choices for advanced CRC treatment 36. Recently, molecule-targeted agents, such as cetuximab,37 panitumumab,38,39 bevacizumab,40 regorafenib41,42 and ramucirumab,43,44 that inhibit RTKs activation have been approved for use in CRC treatment. Downregulation of RTKs’ activity can attenuate tumor cell growth, metastasis, and angiogenesis 45–47.…”

Section: Discussionmentioning

confidence: 99%

<p>MicroRNA-940 restricts the expression of metastasis-associated gene MACC1 and enhances the antitumor effect of Anlotinib on colorectal cancer</p>

Wang¹,

Zhao²,

Zhao³

et al. 2019

OTT

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Background: Metastasis-associated with colon cancer-1 (MACC1) is an important regulator that promotes colorectal cancer (CRC) cells’ proliferation and distant metastasis. Therefore, MACC1 is considered as a promising therapeutic target of CRC. This work aimed to identify the microRNA (miR) targeted to MACC1, and to study the potential of using the particular miR in enhancing the antitumor effect of chemotherapy. Materials and methods: miR prediction was performed in the miR database. The effect of miR-940 on MACC1’s expression was examined by Western blot, and the effect of miR-940 on the expression of genes related to the epithelial–mesenchymal transition (EMT) was identified by quantitative real-time polymerase chain reaction experiments. In vivo growth of CRC cells were analyzed in the nude mice subcutaneous tumor model and CRC liver metastasis model. Results: By using the database, miR-940 was identified to target to the 3ʹUTR of MACC1’s mRNA. Experimentally, transfection of miR-940 decreased the expression of MACC1 in CRC cells and inhibited the EMT process of the transfected cells. MiR-940 also enhanced the inhibitory effect of Anlotinib on CRC cells’ in vivo growth and invasion. Correspondingly, ectopic expression of MACC1 mutant, which does not contain miR-940 binding site, blocked the antitumor effect of miR-940 on CRC cells. Conclusion: MiR-940 restricts the proliferation and invasion of CRC cells by targeting to MACC1’s mRNA, and enhances the antitumor effect of Anlotinib on CRC tumors.

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Cell-Free DNA Profiling to Discover Mechanisms of Exceptional Response to Cabozantinib Plus Panitumumab in a Patient With Treatment Refractory Metastatic Colorectal Cancer

Cited by 15 publications

References 51 publications

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Immune Resistance and EGFR Antagonists in Colorectal Cancer

HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers

<p>MicroRNA-940 restricts the expression of metastasis-associated gene MACC1 and enhances the antitumor effect of Anlotinib on colorectal cancer</p>

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