MEK inhibitor resistance mechanisms and recent developments in combination trials

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.

Download Full-text

DDRE-07. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL INHIBITION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.252 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii62-ii62

Author(s):

Elisa Izquierdo ◽

Diana Carvalho ◽

Alan Mackay ◽

Sara Temelso ◽

Jessica K R Boult ◽

...

Keyword(s):

Drug Exposure ◽

Mapk Pathway ◽

Synergistic Effects ◽

Acquired Resistance ◽

Mek Inhibitor ◽

Resistance Mechanisms ◽

Genetic Alterations ◽

Mesenchymal Transition

Abstract The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples, which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted an observed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.

Download Full-text

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.

Download Full-text

Cell line-specific network models of ER+ breast cancer identify potential PI3Kα inhibitor resistance mechanisms and drug combinations

Cancer Research ◽

10.1158/0008-5472.can-21-1208 ◽

2021 ◽

pp. canres.1208.2021

Author(s):

Jorge Gómez Tejeda Zañudo ◽

Pingping Mao ◽

Clara Alcon ◽

Kailey Kowalski ◽

Gabriela N Johnson ◽

...

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Network Models ◽

Resistance Mechanisms ◽

Drug Combinations ◽

Inhibitor Resistance

Download Full-text

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽

10.3390/cancers12082054 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2054

Author(s):

Elizabeth K. Lee ◽

Ursula A. Matulonis

Keyword(s):

Synthetic Lethality ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Resistance Mechanisms ◽

Parp Inhibition ◽

Combination Therapies ◽

Mechanisms Of Resistance ◽

Damage Repair ◽

Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

Download Full-text

Distribution and validation of genotypic and phenotypic glyphosate and PPO-nhibitor resistance in Palmer amaranth (Amaranthus palmeri) from southwestern Nebraska

Weed Technology ◽

10.1017/wet.2020.74 ◽

2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Maxwel C Oliveira ◽

Darci A Giacomini ◽

Nikola Arsenijevic ◽

Gustavo Vieira ◽

Patrick J Tranel ◽

...

Keyword(s):

Cluster Analysis ◽

Gene Amplification ◽

Cropping Systems ◽

Resistance Mechanism ◽

Geographic Area ◽

Glyphosate Resistance ◽

Resistance Mechanisms ◽

Palmer Amaranth ◽

Resistance Evolution ◽

Inhibitor Resistance

Abstract Failure to control Palmer amaranth with glyphosate and protoporphyrinogen IX oxidase (PPO)-inhibitor herbicides was reported across southwestern Nebraska in 2017. The objectives of this study were to 1) confirm and 2) validate glyphosate and PPO-inhibitor (fomesafen and lactofen) resistance in 51 Palmer amaranth accessions from southwestern Nebraska using genotypic and whole-plant phenotypic assay correlations and cluster analysis, and 3) determine which agronomic practices might be influencing glyphosate resistance in Palmer amaranth accessions in that location. Based on genotypic assay, 88% of 51 accessions contained at least one individual with amplification (>2 copies) of the 5-enolypyruvyl-shikimate-3-phosphate synthase (EPSPS) gene, which confers glyphosate resistance; and/or a mutation in the PPX2 gene, either ΔG210 or R128G, which endows PPO-inhibitor resistance in Palmer amaranth. Cluster analysis and high correlation (0.83) between genotypic and phenotypic assays demonstrated that EPSPS gene amplification is the main glyphosate resistance mechanism in Palmer amaranth accessions from southwestern Nebraska. In contrast, there was poor association between genotypic and phenotypic responses for PPO-inhibitor resistance, which was attributed to segregation for PPO-inhibitor resistance within these accessions and/or the methodology that was adopted herein. Genotypic assays can expedite the process of confirming known glyphosate and PPO-inhibitor resistance mechanisms in Palmer amaranth from southwestern Nebraska and other locations. Phenotypic assays are also a robust method for confirming glyphosate resistance but not necessarily PPO-inhibitor resistance in Palmer amaranth. Moreover, random forest analysis of glyphosate resistance in Palmer amaranth indicated that EPSPS gene amplification, county, and current and previous crops are the main factors influencing glyphosate resistance within that geographic area. Most glyphosate-susceptible Palmer amaranth accessions were found in a few counties in areas with high crop diversity. Results presented here confirm the spread of glyphosate resistance and PPO-inhibitor resistance in Palmer amaranth accessions from southwestern Nebraska and demonstrate that less diverse cropping systems are an important driver of herbicide resistance evolution in Palmer amaranth.

Download Full-text