BRAF Inhibitor Resistance Mechanisms in Metastatic Melanoma: Spectrum and Clinical Impact

Background: Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect: In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.

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A targeted genomic analysis uncovered a large spectrum of acquired resistance mechanisms to BRAF inhibitor therapy in metastatic melanoma patients

Annals of Oncology ◽

10.1093/annonc/mdy047.063 ◽

2018 ◽

Vol 29 ◽

pp. iii25-iii26

Author(s):

B. Louveau ◽

C. Reger de Moura ◽

M. Battistella ◽

A. Sadoux ◽

I. Chami ◽

...

Keyword(s):

Metastatic Melanoma ◽

Acquired Resistance ◽

Braf Inhibitor ◽

Genomic Analysis ◽

Resistance Mechanisms ◽

Inhibitor Therapy ◽

Melanoma Patients

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Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors

eLife ◽

10.7554/elife.19671 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 62

Author(s):

Jean M Mulcahy Levy ◽

Shadi Zahedi ◽

Andrea M Griesinger ◽

Andrew Morin ◽

Kurtis D Davies ◽

...

Keyword(s):

Brain Tumors ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Braf Inhibitor ◽

Pediatric Brain Tumors ◽

Resistance Mechanisms ◽

Cancer Therapies ◽

Clinical Responses ◽

Inhibitor Resistance ◽

Autophagy Inhibition

Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAFV600Emutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAFV600E inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAFV600E brain tumors.

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Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms

European Journal of Cancer ◽

10.1016/j.ejca.2015.08.022 ◽

2015 ◽

Vol 51 (18) ◽

pp. 2792-2799 ◽

Cited By ~ 161

Author(s):

Douglas B. Johnson ◽

Alexander M. Menzies ◽

Lisa Zimmer ◽

Zeynep Eroglu ◽

Fei Ye ◽

...

Keyword(s):

Meta Analysis ◽

Braf Inhibitor ◽

Resistance Mechanisms ◽

Clinical Behaviour ◽

Inhibitor Resistance

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Landscape of genomic alterations (GA) and tumor mutational burden (TMB) in different metastatic melanoma (MM) subtypes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9536 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9536-9536 ◽

Cited By ~ 10

Author(s):

Douglas Buckner Johnson ◽

J. Andrew Carlson ◽

Julia Andrea Elvin ◽

Jo-Anne Vergilio ◽

James Suh ◽

...

Keyword(s):

Kinase Inhibitors ◽

Braf Inhibitor ◽

Resistance Mechanisms ◽

Kinase Domain ◽

Genomic Signatures ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Copy Number Changes ◽

Inhibitor Resistance ◽

Effective Use

9536 Background: MM is a highly targetable malignancy, with both kinase inhibitors and immunotherapies providing meaningful survival benefit. Different subtypes of mm harbor distinct GA that suggest targeted and immunotherapy options. Methods: Comprehensive genomic profiling was performed in 2,197 MMs for up to 315 cancer-related genes plus introns from 28 genes commonly rearranged in cancer on hybrid-capture, adaptor ligation-based libraries (mean coverage depth > 600X). TMB was calculated from ≥1.11 Mb sequenced DNA. We assessed base substitutions, insertions and deletions (short variants; SV), rearrangements, and copy number changes. Results: We assessed 6 subtypes: routine cutaneous (CT; 90%), desmoplastic (DM: 1%), acral lentiginous (AL; 1%), Spitzoid (SP; 1%), mucosal (MC; 2%) and ocular (OC; 5%). Each group harbored characteristic genomic signatures (Table). BRAFwas mutated in 38% of CT of which 92% were SV GA and 8% were amplifications, fusions or cases with > 1 BRAF GA. High TMB in CT and DM is highly prevalent (42% and 83% with > 20 mut/Mb). BRAFGA were less common in AL (18%), MC (15%), and OC (2%). SP GA were dominated by fusions in BRAF (60%) and other kinases. KIT GA were prominent in MC and AL. TMB for MC and OC mm were very low. Key findings include novel drivers of BRAF inhibitor resistance including BRAFinternal rearrangements and kinase domain duplications. Conclusions: In the largest cohort of mm with NGS to date, genomic profiles and TMB differ across mm subtypes. Highly prevalent BRAF GA (including in the SP variant) and high TMB in CT and DM mm permit effective use of targeted and immunotherapies. Although MC and OC have lower BRAF GA frequency and lower TMB, targetable GA can be present. Novel BRAF inhibitor resistance mechanisms were observed. [Table: see text]

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LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance

Oncogene ◽

10.1038/s41388-021-01808-3 ◽

2021 ◽

Author(s):

Ola Billing ◽

Ylva Holmgren ◽

Daniel Nosek ◽

Håkan Hedman ◽

Oskar Hemmingsson

Keyword(s):

Growth Factor Receptor ◽

Braf Inhibitor ◽

Treatment Resistance ◽

Negative Regulator ◽

C Elegans ◽

Rtk Signaling ◽

Egfr Expression ◽

Inhibitor Resistance ◽

Leucine Rich Repeats

AbstractLeucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.

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FGFR Inhibitors in Oncology: Insight on the Management of Toxicities in Clinical Practice

Cancers ◽

10.3390/cancers13122968 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2968

Author(s):

Anuhya Kommalapati ◽

Sri Harsha Tella ◽

Mitesh Borad ◽

Milind Javle ◽

Amit Mahipal

Keyword(s):

Clinical Utility ◽

Fibroblast Growth Factor Receptor ◽

Treatment Guidelines ◽

Growth Factor Receptor ◽

The United States ◽

Resistance Mechanisms ◽

Effective Management ◽

Metastatic Urothelial Carcinoma ◽

Accelerated Approval ◽

Inhibitor Resistance

Fibroblast Growth Factor receptor (FGFR) pathway aberrations have been implicated in approximately 7% of the malignancies. As our knowledge of FGFR aberrations in cancer continues to evolve, FGFR inhibitors emerged as potential targeted therapeutic agents. The promising results of pemigatinib and infigratinib in advanced unresectable cholangiocarcinoma harboring FGFR2 fusions or rearrangement, and erdafitinib in metastatic urothelial carcinoma with FGFR2 and FGFR3 genetic aberrations, lead to their accelerated approval by the United States (USA) FDA. Along with these agents, many phase II/III clinical trials are currently evaluating the use of derazantinib, infigratinib, and futibatinib either alone or in combination with immunotherapy. Despite the encouraging results seen with FGFR inhibitors, resistance mechanisms and side effect profile may limit their clinical utility. A better understanding of the unique FGFR-inhibitor-related toxicities would invariably help us in the prevention and effective management of FGFR-inhibitor-induced adverse events thereby enhancing their clinical benefit. Herein, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. This work would invariably help practicing oncologists to effectively manage the unique toxicities of FGFR inhibitors.

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Deregulated FASN Expression in BRAF Inhibitor-Resistant Melanoma Cells Unveils New Targets for Drug Combinations

Cancers ◽

10.3390/cancers13092284 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2284

Author(s):

Serena Stamatakos ◽

Giovanni Luca Beretta ◽

Elisabetta Vergani ◽

Matteo Dugo ◽

Cristina Corno ◽

...

Keyword(s):

Drug Resistance ◽

Metastatic Melanoma ◽

Mutant Cell ◽

Braf Inhibitor ◽

Cancer Cell Line ◽

Melanoma Cells ◽

Melanoma Progression ◽

Increased Sensitivity ◽

Resistant Cells

Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.

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Distribution of PPX2 Mutations Conferring PPO-Inhibitor Resistance in Palmer Amaranth Populations of Tennessee

Weed Technology ◽

10.1017/wet.2018.59 ◽

2018 ◽

Vol 32 (5) ◽

pp. 592-596 ◽

Cited By ~ 8

Author(s):

J. Drake Copeland ◽

Darci A. Giacomini ◽

Patrick J. Tranel ◽

Garret B. Montgomery ◽

Lawrence E. Steckel

Keyword(s):

Resistance Mechanisms ◽

Palmer Amaranth ◽

The Other ◽

Group 14 ◽

Row Crops ◽

Site Of Action ◽

Inhibitor Resistance ◽

New Mutations

AbstractProtoporphyrinogen IX oxidase (PPO)–inhibiting herbicides (WSSA Group 14) have been used in agronomic row crops for over 50 yr. Broadleaf weeds, including glyphosate-resistant Palmer amaranth, have been controlled by this herbicide site of action PRE and POST. Recently, Palmer amaranth populations were reported resistant to PPO inhibitors in 2011 in Arkansas, in 2015 in Tennessee, and in 2016 in Illinois. Historically, the mechanism for this resistance involves the deletion of a glycine at position 210 (ΔG210) in a PPO enzyme encoded by the PPX2 gene; however, the ΔG210 deletion did not explain all PPO inhibitor–resistant Palmer amaranth in Tennessee populations. Recently, two new mutations within PPX2 (R128G, R128M) that confer resistance to PPO inhibitors were identified in Palmer amaranth. Therefore, research is needed to document the presence and distribution of the three known mutations that confer PPO inhibitor resistance in Tennessee. In 2017, a survey was conducted in 18 fields with Palmer amaranth to determine whether resistance existed and the prevalence of each known mutation in each field. Fomesafen was applied at 265 g ai ha–1 to Palmer amaranth infestations within each field to select for resistant weeds for later analysis. Where resistance was described (70% of surviving plants), the ΔG210 mutation was detected in 47% of resistant plants. The R128G mutation accounted for 42% of resistance, similar to the frequency of the ΔG210 mutation. The R128M mutation was less frequent than the other two mutations, accounting for only 10% of the resistance. All mutations detected in this study were heterozygous. Additionally, no more than one of the three PPX2 mutations were detected in an individual surviving plant. Similar to previous research, about 70% of PPO resistance was accounted for by these three known mutations, leaving about 30% of resistance not characterized in Tennessee populations. Survivors not showing the three known PPO mutations suggest that other resistance mechanisms are present.

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