Heterogeneity of kinase inhibitor resistance mechanisms in GIST

AbstractPrimary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired andde novoresistance to a variety of kinase inhibitors, and found that in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in cilia length seem to be linked to the lack of recruitment of Kif7 and IFT81 to cilia tips, and result in enhanced hedgehog pathway activation. Notably, Kif7 knockdown is sufficient to confer drug resistance in drug sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. The identification of a broad mechanism of pathway-unbiased drug resistance, represents a major advancement in oncology, and helps define a specific and important role for cilia in human cancer.

Download Full-text

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.

Download Full-text

Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer

Cell Reports ◽

10.1016/j.celrep.2018.05.016 ◽

2018 ◽

Vol 23 (10) ◽

pp. 3042-3055 ◽

Cited By ~ 30

Author(s):

Andrew D. Jenks ◽

Simon Vyse ◽

Jocelyn P. Wong ◽

Eleftherios Kostaras ◽

Deborah Keller ◽

...

Keyword(s):

Primary Cilia ◽

Kinase Inhibitor ◽

Resistance Mechanisms ◽

Inhibitor Resistance

Download Full-text

Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib

Cancers ◽

10.3390/cancers13010006 ◽

2020 ◽

Vol 13 (1) ◽

pp. 6

Author(s):

Silvia La Monica ◽

Claudia Fumarola ◽

Daniele Cretella ◽

Mara Bonelli ◽

Roberta Minari ◽

...

Keyword(s):

Cell Lines ◽

Kinase Inhibitor ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Resistance Mechanisms ◽

Resistant Cell ◽

Nsclc Cell ◽

Dual Inhibitor ◽

Nsclc Patients ◽

Egfr Mutated

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.

Download Full-text

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.

Download Full-text

Abstract 1111: MYC promotes tyrosine kinase inhibitor resistance inROS1fusion positive lung cancers

10.1158/1538-7445.am2021-1111 ◽

2021 ◽

Author(s):

Sudarshan R. Iyer ◽

Igor Odintsov ◽

Adam J. Schoenfeld ◽

Hiroki Sato ◽

Evan Siau ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Lung Cancers ◽

Inhibitor Resistance

Download Full-text