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The mechanism and consequences of BRAF inhibitor resistance in melanoma

来源： 发布时间：2023-10-16 11:12:39 浏览次数： 次 【字体：小 大】

Genome Instability & Disease (2023)Cite this article

Abstract

BRAF V600E is a constitutive BRAF (B-raf proto-oncogene, serine/threonine kinase) mutation that accounts for more than 90% of BRAF mutations in melanoma. Vemurafenib is a BRAF V600E selective kinase inhibitor (BRAFi) that is commonly used to treat BRAF V600E melanoma patients. However, vemurafenib treatment-induced resistance occurs in about 50% of patients diagnosed with melanoma, and half of the patients have disease progression within six months. But the mechanism and the consequences of BRAF inhibitor resistance have not been fully elucidated. In this review, we summarize the mechanism and the consequences of BRAF inhibitor vemurafenib resistance in melanoma, aiming to provide a guidance for the intervention of BRAF inhibitor resistance.

Introduction

Cancer begins when a series of gene mutations or other genomic alterations transform a normal cell into a cancer cell. Some of these mutations, referred to as “driver mutations”, encode proteins that drive tumor growth. Most often, cancer develops after a series of mutations occurring in both oncogenes and tumor suppressor genes. Proto-oncogenes are normal genes that encode important proteins in stimulating cell growth and division (Kontomanolis et al., 2020). These genes are primarily active during fetal development and for short periods of time in adults to aid in tissue repair. When mutated, proto-oncogenes become oncogenes and the tumor is about to develop (Lipsick, 2022).

Melanoma is a highly malignant tumor derived from the malignant transformation of melanocytes. Mutations of the proto-oncogene BRAF will result in the continuous production of proteins that stimulate cell proliferation. Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with more than 50% of the patients harboring the BRAF V600E mutation(Davies et al., 2002; Flaherty et al., 2012; Ishimura et al., 2003). Although, currently, there are many drugs targeting BRAF, the emergence of drug resistance greatly reduces the effectiveness of treatment.

Anti-cancer drug resistance is one of the main obstacles in the treatment of cancers and linked to several mechanisms associated with both irreversible genetic mutations and reversible proteomic and epigenetic mechanisms (Karami Fath et al., 2022). Tumor heterogeneity and microenvironment-mediated mechanisms have gained increasing attention since it has been demonstrated that they contribute significantly to the capacity of tumor cells to escape therapeutic effects. However, the way by which drug resistance arises in cancer cells is not yet fully understood (MusiandBongiovanni, 2023). Therefore, anti-cancer drug resistance is a major challenge for advanced cancer treatment. An understanding of the underlying mechanisms and the development of effective strategies against anti-cancer drug resistance are highly desired in the clinical research fields.

Here, we review the roles of BRAF mutations in melanomagenesis and the mechanism of BRAF inhibitor resistance in melanoma, aiming to help with the treatment of melanoma and provide a guidance for the intervention of BRAF inhibitor resistance.

The BRAF mutation and melanomagenesis

Melanoma is the most aggressive skin cancer type that could affect individuals of any age (TianandGuo, 2020). Melanoma develops from the malignant transformation of the melanocytes located in the basal layer of the epidermis. Melanocytes may also be found in the meninges, eyes, ears, gastrointestinal tract, genitourinary system, or other mucosal surfaces. Melanoma is caused by an uncontrolled proliferation of melanocytes, which at first may form a benign lesion, but in time, it may transit to melanoma (Jitian MihuleceaandRotaru, 2023). At the same time, advanced melanoma has a poor prognosis, with a 5-year survival rate being less than 18% in the presence of metastases. Metastatic melanoma can affect virtually any organ of the human body, with the most common sites being the lungs, liver, lymph nodes, skin, and brain.

The BRAF gene is a proto-oncogene on chromosome 7 and becomes an oncogene when mutated. The gene encodes a serine/threonine kinase that drives cell growth (Holderfield et al., 2014). The oncogenic mutations of BRAF were discovered in 2002 and are now known to be important drivers in more than one type of cancer. The BRAF mutation alone is not sufficient for the development of cancer, and at least another mutation is needed for cancer to develop. The BRAF mutation alone can lead only to the development of benign moles. BRAF mutations associated with cancer are almost always acquired mutations, and they are present only in the cancer cells (YilmazandGüven Meşe, 2020).

The promise of molecular targeted therapy for melanoma began with the discovery of somatic mutations in the BRAF gene in more than 50% of melanoma cell lines. In clinical trials, patients treated with BRAF inhibitor (BRAFi) monotherapy had promising response rates and improvement in progression-free survival. But unfortunately, the melanoma cells became resistant very quickly and affected the progression of the disease.

Constitutively activating BRAF mutations are well documented. These have been described to promote tumorigenesis through downstream tumor suppressor inactivation and inhibition of apoptosis. These mutations are also believed to increase the metastatic potential of a tumor (Fecher et al., 2008).

Targeting BRAF plays an important role in skin cancer treatment, but complications usually occur during clinical treatment due to its high anti-cancer drug resistance. In this review, we aim to cover the mechanism of BRAFi resistance.

BRAF Inhibitors

BRAF inhibitors (BRAFi) are medications that target the BRAF pathways in tumor cells (Poulikakos et al., 2022). Unlike chemotherapy drugs, these medications do not “kill” cancer cells, but rather control the growth of a tumor by interrupting the signaling pathway that leads to cell growth and division. As such, they do not “cure” a cancer, but can control the cancer growth for a significant period of time.

Currently, there are several BRAFis that have been approved. These drugs directly attack the mutated BRAF protein (Shi et al., 2012). Vemurafenib is the first FDA-approved inhibitor of the mutated BRAF gene. Vemurafenib (PLX4032) was developed as a low-molecular-weight molecule for the inhibition of the mutated BRAF, and it selectively binds to the ATP-binding site of the BRAF V600E kinase and inhibits its activity.

Vemurafenib further inhibits ERK phosphorylation and cell proliferation in BRAF-mutant cell lines (GarbeandEigentler, 2018). In the clinical trials, vemurafenib-treated melanoma patients achieved rapid and unprecedented tumor shrinkage, higher response rates, progression-free survival, and overall survival. (Bollag et al., 2012). However, the durability of the vemurafenib response is limited by acquired drug resistance (DummerandFlaherty, 2012). Acquired resistance to BRAFi, such as vemurafenib, is limiting the benefits of long-term targeted therapy for patients with malignant melanomas (Sinnberg et al., 2016).

The mechanism of BRAFi resistance

The MAPK signaling pathway

The mechanisms of acquired resistance to the BRAFi therapy are diverse and include the reactivation of oncogenic signaling using the MAPK (Mitogen-Activated Protein Kinase) pathway in approximately two-thirds of cases (YilmazandGüven Meşe, 2020).

The Mitogen-Activated Protein Kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation, and migration (KnightandIrving, 2014). The role of the MAPK pathway in cancer has been well recognized (Santarpia et al., 2012), (Cseh et al., 2014). The activating BRAF mutation V600E is the most important for the activation of the RAS/RAF/MEK/ERK(Rat sarcoma viral oncogene homolog/Rapidly Accelerated Fibrosarcoma/Mitogen-activated protein kinase/Extracellular signal-regulated kinase) signaling pathway in melanoma (Long et al., 2011). Increased MAPK reactivation has been frequently observed in progressing melanomas, providing the rationale for the co-targeting of BRAF and downstream MEK. When any part of this pathway is overactive in a tumor, it helps cancer growth and metastasis. BRAF activates the MAPK Extracellular Signal-regulated Kinase (MEK), which in turn phosphorylates and activates ERK1 and ERK2 (Extracellular Signal-regulated Kinases 1 and 2) (MenziesandLong, 2014).

Recent studies have shown that in addition to the dependence on the MAPK pathway, over-expression of receptors such as PDGFRβ (Platelet-Derived Growth Factor Beta) or the IGF-1R (Insulin Growth Factor-1 Receptor), which are upstream of the PI3K/AKT pathway, may play important roles in the resistance to BRAF inhibitors (Chan et al., 2017).

Mohammad Atefi et al. also investigated the activity of the AKT pathway and its possible effect on the resistance of melanoma cells to inhibitors of the MAPK pathway. They examined whether the induction of AKT signaling by inhibitors of the MAPK pathway may in part be caused by the activation of the feedback mechanisms originating from the downstream factors in the AKT pathway. Their results suggest that most BRAF V600E mutant melanomas not responding to vemurafenib are also cross-resistant to single-agent MEK inhibitors (Atefi et al., 2011).

Previous data from other groups have demonstrated the superior antitumor activity of combining MAPK and PI3K/AKT/mTOR (Mitogen-activated Protein Kinase/Phosphoinositide 3-Kinase) pathway inhibitors in BRAF V600E mutant cell lines, by testing this concept in isogenic pairs of sensitive and acquired resistant cell lines, and in cell lines established directly from patients progressing after a response on vemurafenib. Therefore, investigations are aiming to elucidate the molecular mechanisms that result in primary or acquired resistance to vemurafenib and sensitivity to combined MAPK and AKT/mTOR pathway inhibition, which would provide useful biomarkers to rationally choose the most appropriate therapy in BRAF V600E mutant melanomas resistant to vemurafenib (Atefi et al., 2011).

Most of the mechanisms leading to the onset of resistance rely upon the reactivation of the MAPK pathway itself. Paradoxically, reactivation of the MAPK pathway may be driven by mutations in NRAS (Neuroblastoma v-Ras oncogene homolog) or MEK. Besides reactivation of the MAPK cascade, resistance to BRAFi can be mediated by activation of the bypass PI3K/AKT/mTOR pathway (Acciardo et al., 2018).

Combination therapy of MEK and BRAF inhibitors results in an extension of the time to resistance, which will lead to longer overall survival of treated patients. Despite the improvements in terms of longer progression-free survival and reduced toxicities, the benefit provided by combined BRAF/MEK targeting is still transient, due to the development of resistance within 6–9  months post the initiation of BRAFi treatment (Ascierto et al., 2012).

The EGF/EGFR signaling pathway

EGFR (Epidermal Growth Factor Receptor) is a gene that encodes the epidermal growth factor receptor protein (Voldborg et al., 1997). BRAFi resistance commonly correlates with a high level of EGFR expression and a poor prognosis (LuebkerandKoepsell, 2019). EGFR activation after phosphorylation is more highly associated with resistance and EMT (epithelial–mesenchymal) transition, notably after reactivation of the ERK pathway.

The EGFR–SFK–STAT3 (Epidermal Growth Factor Receptor–Src Family Kinase–Signal Transducer and Activator of Transcription 3) signaling pathway was upregulated in cells with acquired resistance to vemurafenib (Becker et al., 2014). BRAF V600E inhibition suppresses MAPK signaling, which in turn downregulates the EGFR phosphatase, resulting in sustained EGFR phosphorylation and enhanced EGFR activity (Karami Fath et al.). Anaïs Paris et al. (Paris et al., 2022) underscored that Aryl hydrocarbon Receptor (AhR)-dependent activation of SRC (SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase) mediates the activation of the EGFR, and they showed that activation of SRC leads to the reactivation of EGFR after its phosphorylation in BRAFi-resistant melanoma cell lines.

Maria R Girotti et al. (Girotti et al., 2013) generated cell lines resistant to BRAFi and showed that the EGF–SRC–STAT3(Epidermal Growth Factor–Proto-oncogene tyrosine-protein kinase Src–Signal Transducer and Activator of Transcription 3) signaling pathway was upregulated in BRAFi-resistant melanoma cells. In addition to driving the proliferation of resistant cells, this pathway also stimulated invasion and metastasis. Data from Maria R Girotti et al. showed that BRAFi-mediated activation of EGFR/SFK/STAT3(Epidermal Growth Factor Receptor/Src Family Kinases/Signal Transducer and Activator of Transcription 3) signaling can mediate resistance in BRAF-mutant melanoma patients (Girotti et al., 2013).

The IL-6/STAT3 signaling pathway

One target of particular interest for melanoma is the STAT3 protein. STAT3 is a critical factor that regulates the differentiation and function of immunosuppressive cell subsets present in patients with advanced cancer, including myeloid-derived suppressor cells or regulatory T cells (Yu et al., 2009). STAT3 represents an important therapeutic target in melanoma, due to its dual effects on malignant cell growth and host immune function (Lesinski, 2013).

STAT3 is constitutively activated in many human cancers where it functions as a critical mediator of oncogenic signaling through transcriptional activation of genes encoding apoptosis inhibitors (e.g., Bcl-x(L), Mcl-1), cell-cycle regulators (e.g., cyclin D1 and c-Myc), and inducers of angiogenesis (e.g., vascular endothelial growth factor) (JingandTweardy, 2005).

BCL-2 family proteins are major regulators of the apoptotic threshold and are deregulated in many cancer types (Beroukhim et al., 2010). The anti-apoptotic members of the BCL-2 family, known as multi-domain anti-apoptotic proteins, include: BCL-2 (BCL2 Apoptosis Regulator), BCL2-L1 (BCL2 Like 1, also known as BCL- XL), BCL2-L2 (BCL2 Like 2, also known as BCL-W), MCL-1(MCL1 Apoptosis Regulator, BCL2 Family Member), and BCL-2A1 (BCL2-Related Protein A1, also known as BFL-1). In melanoma, altered BCL-2, BCL-XL, and MCL-1 expression are associated with the malignant transformation of melanocytic cells and progression to melanoma (Saenz-Santamaría et al., 1994). In addition, increased expression of BCL-XL is associated with a poor prognosis in patients with melanoma and elevated BCL-2 and BCL-XL are also associated with a poor response to therapy.

The oncogenic activities of Mcl-1 have drawn particular attention in recent years, due to frequent amplifications of the Mcl-1 gene in about 40% of cancer cells of different origins (Beroukhim et al., 2010). Often high Mcl-1 expression was correlated with tumor progression and drug resistance (Peng et al., 2023).

As a rational target in melanoma to complement BRAF-targeted therapy, a recent report showed that STAT3 is a central regulator of BRAF V600E-mediated Mcl-1 transcription and melanoma cell survival (Becker et al., 2014). STAT3-targeted therapies are effective in cells that have acquired resistance to the BRAF inhibitor vemurafenib (Lesinski, 2013). Treatment with a STAT3 inhibitor and silencing STAT3 via siRNA was effective in inhibiting growth in both vemurafenib-sensitive or vemurafenib-resistant melanoma cells (Liu et al., 2013).

Niu et al. (Niu et al., 2002) demonstrated that STAT3 is constitutively activated in a majority of human melanoma cell lines and tumor specimens. Src tyrosine kinase inhibitors disrupt STAT3 DNA-binding activity and induce tumor cell death. Therefore, directly blocking STAT3 DNA-binding by a dominant-negative STAT3 protein leads to melanoma cell apoptosis. These findings suggest that targeting STAT3 and/or Src may represent an effective therapy for melanoma (Niu et al., 2002).

Other pathways

Recent studies have implicated the PI3K/AKT (Phosphoinositide Kinase-3/Akt kinase) signaling pathway in the development of BRAFi resistance. A high phosphorylated AKT (p-AKT) level in cell lines and biopsies appears to predict resistance to vemurafenib (Luo et al., 2016).

In addition, Lehraiki et al. identified CD271(Nerve Growth Factor Receptor) as a new mechanism of acquired resistance of melanoma cells to BRAFi that involves Tumor Necrosis Factor-Alpha (TNFα)/NF-κB pathway activation and sustained CD271 expression. CD271 confers resistance to BRAFi in melanoma cells. The expression of CD271 is increased by BRAFi through a stimulation of TNFα secretion that leads to NF-κB signaling pathway activation. CD271 is upregulated in a subset of BRAFi-resistant melanoma cells. The inhibition of the TNFα/NF-κB pathway and CD271 silencing restore the BRAFi sensitivity of resistant melanoma cells (Lehraiki et al., 2015).

The elevated levels of endogenous BRAF V600E in A375 cells might correlate with the resistance conferred by PLX4720-resistant alleles (Shi et al., 2012; Wagenaar et al., 2014). Overexpression of COT (Carnitine O-octanoyltransferase), NRAS mutations, or the MEK1C121S mutation has been shown to mediate acquired BRAFi resistance (Johannessen et al., 2010), (Wagle et al., 2011).

Transcription factors, such as the master regulator of the melanocytic lineage, the MITF(Microphthalmia-associated Transcription Factor) play a critical role in directing melanoma cell plasticity (GodingandArnheiter, 2019). While MITF high activity is associated with melanocyte differentiation and drives melanoma proliferation (Kotmayer et al., 2022), the MITF low activity is associated with drug resistance (Nwabo Kamdje et al., 2014), supporting the notion of transcriptional balance.

Aryl hydrocarbon receptor (AhR) (Karami Fath et al.) transcription factor is also constitutively activated in a subset of melanoma cells, and it promotes the de-differentiation of melanoma cells and the expression of BRAFi-resistant genes (Paris et al., 2022). AhR is markedly expressed in highly de-differentiated, resistant, and invasive melanoma cells, mediating resistance to BRAFi (Moreau et al., 2021). The AhR/SRC (Steroid Receptor Coactivator) axis orchestrates cell plasticity, constituting an important therapeutic vulnerability. It may be useful for future clinical studies to target the AhR-dependent SRC/FAK/EGFR axis in combination with BRAFi/MEKi double blockade to re-sensitize melanoma to standard melanoma treatment and counteract resistance (Paris et al., 2022).

Among the several molecular effectors involved in drug resistance and, in particular, in BRAF resistance to vemurafenib, the uPAR(Urokinase Plasminogen Activator Receptor) might play a crucial role given its involvement in intracellular signaling, activation of latent growth factors, extracellular matrix degradation, and tumor neo-angiogenesis (Dass et al., 2008).

Concerning BRAF-mutant melanoma, many studies have pointed out the role of epigenetic mechanisms, mainly through HDAC (Histone Deacetylase), in resistance to BRAF and MEK inhibition (Booth et al., 2017),(Emmons et al., 2019). This suggests the possibility of preventing the onset of resistance using HDACi (Madorsky Rowdo et al., 2020).

The generation of resistance mechanisms mainly includes genetic resistance and non-genetic resistance. Genetic resistance mechanisms most commonly result in reactivation of the MAPK pathway through NRAS or KRAS (Kirsten rat sarcoma virus) mutations, V600E/KBRAF amplification, or alternative splicing. In contrast, non-genetic resistance mechanisms often result in MAPK pathway-redundant survival with upregulated expression of receptor tyrosine kinases such as PDGFRβ (Platelet-derived growth factor receptor beta) (Hernandez-Davies et al., 2015). Resistance to BRAF inhibitors proceeds through different genetic routes mainly via mutation, amplification mechanisms, leading to reactivation of the MAPK pathway or MAPK-redundant signaling pathway such as activation of the PI3K/AKT pathway, along with the upregulation of Tyrosine Kinase Receptors (TKRs; EGFR, IGF-1R(Insulin Like Growth Factor-1 Receptor), PDGFR(Platelet-Derived Growth Factor Receptor), AXL(AXL Receptor Tyrosine Kinase), etc.) (ArozarenaandWellbrock, 2017). In addition to these acquired genetic alterations, a new concept of resistance has emerged based on the capacity of melanoma cells to undergo transcriptomic reprogramming. Single-cell transcriptomic analysis showed that the adaptive response to BRAFi is diverse, leading to the generation of a gradient of de-differentiated cell states from melanocytic to neural crest state (Rambow et al., 2018).

However, some mutations are independent of downstream pathways. Overexpressed genes in BRAFi-resistant cells are often associated with growth factors and their receptors, cell adhesion molecules, and extracellular matrix binding. Common mutations involve effects onRTKs, such as EGFR, PDGFR, HGF (Hepatocyte Growth Factor), or IGF (Insulin-like Growth Factor) Receptors, which in turn activate parallel pathways. Research has shown extensive redundancy in RTK-mediated signaling pathways, whereby a broad range of widely expressed RTKs are upregulated in cells with BRAFi resistance. These changes are mediated post-translationally via the inhibition of proteolytic “shedding” of cell surface receptors. This shedding is a normal part of the negative feedback loop that limits intracellular signaling, but is blocked by BRAF inhibitors. As a result, there is an increase in cell surface receptor levels in the tumor during treatment, causing activation or enhancement of alternative signaling pathways.

Consequences of the BRAFi resistance–metastasis/recurrence

Metastatic and drug-resistant melanoma are leading causes of skin cancer-associated death (Reddi et al., 2022). Accumulating evidence has indicated that vemurafenib treatment induced selective pressure to promote melanoma cell migration, invasion, and metastasis (Paraiso et al., 2015) (Manzano et al., 2016). However, the mechanism by which vemurafenib induced melanoma invasion and metastasis is still not completely understood.

BRAFi resistance could activate the tyrosine kinase signaling pathway to induce distant metastasis.

PYK2 (Proline-rich Tyrosine Kinase 2) was critical for invadopodia formation and cell invasion in melanomas. Shen Yang et al.(Shen et al., 2021) showed that the PYK2 kinase was activated by vemurafenib treatment and was required for vemurafenib-induced invadopodia formation and cell invasion in vemurafenib-resistant melanomas. They also found that STIM1(Stromal Interaction Molecule 1) is highly expressed in vemurafenib-resistant cells, and subsequently activates the downstream PYK2–SRC signaling axis, thereby initiating the formation of invasive invadopodia, leading to tumor metastasis caused by drug resistance (Yan et al., 2023).

The tyrosine kinase receptor AXL is a member of the TAM family with the high-affinity ligand GAS6 (growth arrest-specific protein 6). The Gas6/AXL signaling pathway is associated with tumor cell growth, metastasis, invasion, epithelial–mesenchymal transition, angiogenesis, drug resistance, immune regulation, and stem cell maintenance (Zhu et al., 2019). The Gas6/AXL signaling pathway could activate AKT in wild-type PTEN(Phosphatase and Tensin Homolog) melanoma (Zuo et al., 2018); high levels of AXL, together with low levels of MITF, are common in BRAF-mutant melanomas and are associated with early resistance to targeted therapies (Müller et al., 2014).

BRAFi resistance could also enhance angiogenesis, and consequently melanoma progression, by stimulating cancer-associated macrophages to produce, with a paradoxical activation of the MAPK pathway, VEGF, which stimulates melanoma cell growth and recurrence (Wang et al., 2015). The tumor microenvironment could, therefore, determine the innate resistance to BRAFi by secreting HGF (Hepatocyte Growth Factor), which activates MAPK and PI3K/AKT through the MET receptor (Straussman et al., 2012).

Conclusions and future perspectives

In summary, the BRAF V600E mutation induces melanoma and targeting BRAF has remarkably improved the survival of melanoma patients with oncogenic BRAF mutations. However, BRAF inhibitor vemurafenib resistance greatly hinders the clinical application of vemurafenib. The vemurafenib resistance feedback mechanism is activated by MAPK, EGF/EGFR, IL6/STAT3 pathways to overcome chemotherapy (Fig. 1). Meanwhile, vemurafenib resistance can also induce transcriptional reprogramming to overcome vemurafenib therapeutic effects and induce distant metastasis or recurrence. Identification of potential targets for vemurafenib combination therapy is urgent and will improve the therapeutic efficiency of BRAF inhibitors in melanoma patients.

Fig. 1figure 1

Vemurafenib resistance reactivates multiple pathways to overcome therapeutic efficiency(Drug sensitive)

: reduce;: increase;: phosphorylation;: dephosphorylation;

When tumor cells were treated with vemurafenib, MAPK signaling was inhibited, EGFR phosphatase expression was increased, EGFR was dephosphorylated, and EGFR activity was reduced. IL6/STAT3, mTOR signaling was attenuated, reducing drug resistance, metastasis, tumor recurrence, and anti-apoptotic gene expression.

BRAF mutations play a pivotal role in the management of both advanced and completely resected melanoma patients; thus, special attention should be addressed to the detection of BRAF mutations, aiming to avoid the risk and under-treatment of false-negative cases. Deepening knowledge about mechanisms underlying resistance to currently approved preclinical and clinical studies, and even going back to molecular pathways, is necessary for improving outcomes in BRAF-mutant patients.

Further investigations of potential targets for combined therapy or immunotherapy for melanoma are needed to help with the treatment and prevention of cancer.

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Acknowledgements

We thank Dr. Jing Li for the critical reading of the manuscript. This work was supported by the National Natural Science Foundation of China (82273460, 32260167), the Yunnan Applied Basic Research Projects (202101AV070002), a grant (Grant No. KLTIPT-2023-02) from Key Laboratory of Tumor Immunological Prevention and Treatment in Yunnan Province, Yan'an Hospital Affiliated to Kunming Medical University, Kunming and grants (Grant No. 2023Y0222) from Yunnan University.

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  1. Ksenia Golub, Weiyu Bai, and Zhimeng Zhang have contributed equally to this work.

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  1. Center for Life Sciences, School of Life Sciences, State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, Yunnan University, Kunming, China

    Ksenia Golub, Weiyu Bai, Zhimeng Zhang, Huilin Xiao, Rongyuan Sun, Junling Shen & Jianwei Sun

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KG and JS were responsible for the study concept and design. KG, WB, ZZ, HX and RS drafted the manuscript. JS and JS revised and edited the manuscript. All authors contributed to this review and approved the submitted version.

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Correspondence to Junling Shen or Jianwei Sun.

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Golub, K., Bai, W., Zhang, Z. et al. The mechanism and consequences of BRAF inhibitor resistance in melanoma. GENOME INSTAB. DIS. (2023). https://doi.org/10.1007/s42764-023-00105-5

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  • Received08 June 2023

  • Revised07 July 2023

  • Accepted10 July 2023

  • Published31 July 2023

  • DOIhttps://doi.org/10.1007/s42764-023-00105-5

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Keywords

  • BRAF mutation

  • BRAFi

  • Drug resistance

  • EGFR

  • MAPK

  • STAT3

  • Metastasis


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