RAS and BRAF in the foreground for non-small cell lung cancer and colorectal cancer: Similarities and main differences for prognosis and therapies

Giopanou, Ioanna; Pintzas, Alexander

doi:10.1016/j.critrevonc.2019.102859

Cited by 14 publications

(10 citation statements)

References 105 publications

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“…EGFR-targeted therapy can become ineffective, due to the outgrowth of KRAS mutant subpopulations. This was first demonstrated for colorectal cancer [9], which has a cancer driver mutational profile similar to lung cancer [28]. Parallel to observations for colorectal cancer, our previous work showed that KRAS mutant subpopulations are prevalent in lung adenocarcinomas [29].…”

Section: Introductionsupporting

confidence: 67%

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

et al. 2020

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A model that recapitulates development of acquired therapeutic resistance is needed to improve oncology drug development and patient outcomes. To achieve this end, we established methods for the preparation and growth of spheroids from primary human lung adenocarcinomas, including methods to culture, passage, monitor growth, and evaluate changes in mutational profile over time. Primary lung tumor spheroids were cultured in Matrigel ® with varying concentrations of erlotinib, a small molecule kinase inhibitor of epidermal growth factor receptor (EGFR) that is ineffective against KRAS mutant cells. Subtle changes in spheroid size and number were observed within the first two weeks of culture. Spheroids were cultured for up to 24 weeks, during which time interactions between different cell types, movement, and assembly into heterogeneous organoid structures were documented. Allele-specific competitive blocker PCR (ACB-PCR) was used to quantify low frequency BRAF V600E, KRAS G12D, KRAS G12V, and PIK3CA H1047R mutant subpopulations in tumor tissue residue (TR) samples and cultured spheroids. Mutant subpopulations, including multiple mutant subpopulations, were quite prevalent. Twelve examples of mutant enrichment were found in eight of the 14 tumors analyzed, based on the criteria that a statistically-significant increase in mutant fraction was observed relative to both the TR and the no-erlotinib control. Of the mutants quantified in erlotinib-treated cultures, PIK3CA H1047 mutant subpopulations increased most often (5/14 tumors), which is consistent with clinical observations. Thus, this ex vivo lung tumor spheroid model replicates the cellular and mutational tumor heterogeneity of human lung adenocarcinomas and can be used to assess the outgrowth of mutant subpopulations. Spheroid cultures with characterized mutant subpopulations could be used to investigate the efficacy of lung cancer combination therapies.

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Section: Introductionsupporting

confidence: 67%

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

et al. 2020

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“…A number of different experiences have been reported regarding treatment for BRAF-mutated advanced NSCLC patients (Giopanou and Pintzas, 2020). Cardarella et al reported that advanced NSCLC patients with BRAF mutations (p.V600E or non-p.V600E) treated with the platinum-based combination approach did not show a significant difference in PFS and OS to BRAF wild-type patients (Cardarella et al, 2013) Interestingly, BRAF exon 15 p.V600E-mutated patients showed a shorter PFS than non-p.V600E-mutated patients (4.1 vs. 8.9 months; p = 0.297) (Cardarella et al, 2013).…”

Section: Lung Cancermentioning

confidence: 99%

BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients

Malapelle

Rossi

Pisapia

et al. 2020

Critical Reviews in Oncology/Hematology

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In the era of personalized medicine, BRAF mutational assessment is mandatory in advanced-stage melanoma and non-small cell lung cancer (NSCLC) patients. The identification of actionable mutations is crucial for the adequate management of these patients. To date various drugs have been implemented in clinical practice. Similarly, various methods may be adopted for the identification of BRAF mutations. Here, we briefly review the current literature on BRAF in melanoma and NSCLC, focusing attention in particular on the different methods and drugs adopted in these patients. In addition, an overview of the real-world practice in different Italian laboratories with high expertise in molecular predictive pathology testing is provided.

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“…NRAS mutations yield similar effects to KRAS activation and are also predictors of anti-EGFR treatment resistance [ 64 ]. Besides its predictive role for absence of response to anti-EGFR therapy, RAS mutation also has a negative prognostic impact in CRC, being related with right-sided colon tumors, advanced disease, poor differentiation, and presence of liver metastases [ 65 ].…”

Section: Colorectal Cancermentioning

confidence: 99%

Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors

et al. 2021

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Activating mutations in RAS family proteins are found in ~25% of all human cancers. Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform. Historically, KRAS has been acknowledged as “undruggable”, largely because the RAS proteins do not appear to present suitable pockets to which small inhibitory molecules can bind. However, this scenario has changed over the last years with the advent of novel KRAS inhibitors. In this review, we describe the role of KRAS mutation across different solid tumors, providing data on novel KRAS inhibitors currently under development and an updated overview of ongoing research in this field. A literature search was performed to select papers, abstracts, and oral presentation on KRAS inhibitory strategies in KRAS mutated solid tumors. Overall, the most promising therapeutic results have been obtained with molecules targeting KRAS G12C, thus paving the way for a significant therapeutic improvement in non-small cell lung cancer. Unfortunately, KRAS G12C mutation is rather uncommon in other solid tumors, namely pancreatic ductal adenocarcinoma and colorectal cancer. Several combination strategies are currently under evaluation in clinical trials, in order to bypass the resistance mechanisms responsible for the intrinsic resistance of mutated KRAS to the main therapeutic strategies adopted to date. Results suggest that the therapeutic scenario of KRAS has started to change, and further research will bring therapeutic results in this field.

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RAS and BRAF in the foreground for non-small cell lung cancer and colorectal cancer: Similarities and main differences for prognosis and therapies

Cited by 14 publications

References 105 publications

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

BRAF as a positive predictive biomarker: Focus on lung cancer and melanoma patients

Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors

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