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Development of Chemoresistance to Targeted Therapies: Alterations of Cell Signaling, & the Kinome [11.4.1.2]

 

Curator, Reporter: Stephen J. Williams, Ph.D.

The advent of molecular targeted therapies like Imatinib (Gleevec), and other tyrosine kinase inhibitors (TKI) has been transformative to cancer therapy. However, as with all chemotherapeutics, including radiation therapy, the development of chemo-resistance toward personalized, molecular therapies has been disastrous to the successful treatment of cancer. The fact that chemo-resistance develops to personalized therapies was a serious disappointment to clinicians (although most expected this to be the case) but more surprisingly it was the rapidity of onset and speed of early reported cases which may have been the biggest shocker.

A post on resistance to other TKIs (to EGFR and ALK) can be seen here: https://pharmaceuticalintelligence.com/2013/11/01/resistance-to-receptor-of-tyrosine-kinase/

History of Development of Resistance to Imatinib (Gleevec)

The Melo group published a paper in Blood showing that short exposure to STI571 (imatinib; trade name Gleevec®) could result in drug resistant clones

Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood. 2000 Aug 1;96(3):1070-9.

Mahon FX1, Deininger MW, Schultheis B, Chabrol J, Reiffers J, Goldman JM, Melo JV.

Abstract

Targeting the tyrosine kinase activity of Bcr-Abl with STI571 is an attractive therapeutic strategy in chronic myelogenous leukemia (CML). A few CML cell lines and primary progenitors are, however, resistant to this compound. We investigated the mechanism of this resistance in clones of the murine BaF/3 cells transfected with BCR-ABL and in 4 human cell lines from which sensitive (s) and resistant (r) clones were generated by various methods. Although the resistant cells were able to survive in the presence of STI571, their proliferation was approximately 30% lower than that of their sensitive counterparts in the absence of the compound. The concentration of STI571 needed for a 50% reduction in viable cells after a 3-day exposure was on average 10 times higher in the resistant (2-3 micromol/L) than in the sensitive (0.2-0.25 micromol/L) clones. The mechanism of resistance to STI571 varied among the cell lines. Thus, in Baf/BCR-ABL-r, LAMA84-r, and AR230-r, there was up-regulation of the Bcr-Abl protein associated with amplification of the BCR-ABL gene. In K562-r, there was no Bcr-Abl overexpression, but the IC(50) for the inhibition of Bcr-Abl autophosphorylation was increased in the resistant clones. Sequencing of the Abl kinase domain revealed no mutations. The multidrug resistance P-glycoprotein (Pgp) was overexpressed in LAMA84-r, indicating that at least 2 mechanisms of resistance operate in this cell line. KCL22-r showed neither Bcr-Abl up-regulation nor a higher threshold for tyrosine kinase inhibition by STI571. We conclude that BCR-ABL-positive cells can evade the inhibitory effect of STI571 by different mechanisms, such as Bcr-Abl overexpression, reduced intake mediated by Pgp, and, possibly, acquisition of compensatory mutations in genes other than BCR-ABL.

mellobcrablresistamplification

FISH analysis of AR230 and LAMA84 sensitive and resistant clones, with probes for the ABL (red signal) and theBCR (green signal) genes. BCR-ABL is identified as a red–green or yellow fused signal. Adapted from Mahon et al., Blood 2000; 96(3):1070-9.

This rapid onset of imatinib resistance also see in the clinic and more prominent in advance disease

From NCCN 2nd Annual Congress: Hematologic Malignancies – Update on Primary Therapy, Second-Line Therapy, and New Agents for Chronic Myelogenous Leukemia (Slides with Transcript)

http://www.medscape.org/viewarticle/564097

There is some evidence that even looking earlier makes some sense in determining what the prognosis is. This is from Timothy Hughes’ group in Adelaide, and he is looking at an earlier molecular time point, 3 months after initiation of therapy. And what you have done here is you have taken the 3-month mark and you have said, “Well, based on your response at 3 months, what is your likelihood that in the future you will either get a major molecular response or become resistant?”

3monthimitanibresist

If you look at the accumulation of imatinib resistance to find if it is either initially not responding or becoming resistant after a good response, it goes up with type of disease and phase of disease. So if you look at patients who have early chronic phase disease — that is, they start getting imatinib less than a year from the diagnosis — their chance of failure is pretty low. With later disease — they are in a chronic phase but they have had disease more than a year before they get imatinib — it is higher. If you see patients with accelerated phase or blast crisis, the chances are that they will fail sometime in the future.

speed of imitinib resistance

Therefore, because not all resistant samples show gene amplification of Bcr/Abl and the rapidity of onset of resistance, many feel that there are other mechanisms of resistance at play, like kinome plasticity.

Kinome Plasticity Contributes to TKI resistance

Beyond gene amplification, other mechanisms of imitanib and other tyrosine kinase inhibitors (TKI) include alterations in compensatory signaling pathways. This can be referred to as kinome plasticity and is explained in the following abstracts from the AACR 2015 meeting.

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Georg E Winter, Uwe Rix, Scott M Carlson, Karoline V Gleixner, Florian Grebien, Manuela Gridling, André C Müller, Florian P Breitwieser, Martin Bilban, Jacques Colinge, Peter Valent, Keiryn L Bennett, Forest M White & Giulio Superti-Furga. Nature Chemical Biology 8,905–912(2012)

Occurrence of the BCR-ABLT315I gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABLT315I. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABLT315I CML cells on c-Myc through nonobvious off targets.

nchembio.1085-F2kinomegleevecresistance

Please see VIDEO and SLIDESHARE of a roundtable Expert Discussion on CML

Curated Content From the 2015 AACR National Meeting on Drug Resistance Mechanisms and tyrosine kinase inhibitors

Session Title: Mechanisms of Resistance: From Signaling Pathways to Stem Cells
Session Type: Major Symposium
Session Start/End Time: Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
Location: Terrace Ballroom II-III (400 Level), Pennsylvania Convention Center
CME: CME-Designated
CME/CE Hours: 2
Session Description: Even the most effective cancer therapies are limited due to the development of one or more resistance mechanisms. Acquired resistance to targeted therapies can, in some cases, be attributed to the selective propagation of a small population of intrinsically resistant cells. However, there is also evidence that cancer drugs themselves can drive resistance by triggering the biochemical- or genetic-reprogramming of cells within the tumor or its microenvironment. Therefore, understanding drug resistance at the molecular and biological levels may enable the selection of specific drug combinations to counteract these adaptive responses. This symposium will explore some of the recent advances addressing the molecular basis of cancer cell drug resistance. We will address how tumor cell signaling pathways become rewired to facilitate tumor cell survival in the face of some of our most promising cancer drugs. Another topic to be discussed involves how drugs select for or induce the reprogramming of tumor cells toward a stem-like, drug resistant fate. By targeting the molecular driver(s) of rewired signaling pathways and/or cancer stemness it may be possible to select drug combinations that prevent the reprogramming of tumors and thereby delay or eliminate the onset of drug resistance.
Presentations:
Chairperson
Tuesday, Apr 21, 2015, 10:30 AM -12:30 PM
David A. Cheresh. UCSD Moores Cancer Center, La Jolla, CA
Introduction
Tuesday, Apr 21, 2015, 10:30 AM -10:40 AM
Resistance to tyrosine kinase inhibitors: Heterogeneity and therapeutic strategies.
Tuesday, Apr 21, 2015, 10:40 AM -10:55 AM
Jeffrey A. Engelman. Massachusetts General Hospital, Boston, MA
Discussion
Tuesday, Apr 21, 2015, 10:55 AM -11:00 AM
NG04: Clinical acquired resistance to RAF inhibitor combinations in BRAF mutant colorectal cancer through MAPK pathway alterations
Tuesday, Apr 21, 2015, 11:00 AM -11:15 AM
Ryan B. Corcoran, Leanne G. Ahronian, Eliezer Van Allen, Erin M. Coffee, Nikhil Wagle, Eunice L. Kwak, Jason E. Faris, A. John Iafrate, Levi A. Garraway, Jeffrey A. Engelman. Massachusetts General Hospital Cancer Center, Boston, MA, Dana-Farber Cancer Institute, Boston, MA
Discussion
Tuesday, Apr 21, 2015, 11:15 AM -11:20 AM
SY27-02: Tumour heterogeneity and therapy resistance in melanoma
Tuesday, Apr 21, 2015, 11:20 AM -11:35 AM
Claudia Wellbrock. Univ. of Manchester, Manchester, United Kingdom
Discussion
Tuesday, Apr 21, 2015, 11:35 AM -11:40 AM
SY27-03: Breast cancer stem cell state transitions mediate therapeutic resistance
Tuesday, Apr 21, 2015, 11:40 AM -11:55 AM
Max S. Wicha. University of Michigan, Comprehensive Cancer Center, Ann Arbor, MI
Discussion
Tuesday, Apr 21, 2015, 11:55 AM -12:00 PM
SY27-04: Induction of cancer stemness and drug resistance by EGFR blockade
Tuesday, Apr 21, 2015, 12:00 PM -12:15 PM
David A. Cheresh. UCSD Moores Cancer Center, La Jolla, CA
Discussion
Tuesday, Apr 21, 2015, 12:15 PM -12:20 PM
General Discussion
Tuesday, Apr 21, 2015, 12:20 PM -12:30 PM

Targeting Macromolecular Signaling Complexes 
Room 115, Pennsylvania Convention Center

Drug Resistance 
Hall A (200 Level), Pennsylvania Convention Center
Resistance to Pathway-Targeted Therapeutics 1 
Section 33

Molecular Mechanisms of Sensitivity or Resistance to Pathway-Targeted Agents 
Room 118, Pennsylvania Convention Center

Targeting Signaling Pathways in Cancer 
Room 204, Pennsylvania Convention Center
Exploiting the MAPK Pathway in Cancer 
Room 115, Pennsylvania Convention Center

PLEASE see the attached WORD file which includes ALL abstracts, posters, and talks on this subject from the AACR 2015 national meeting BELOW

 AACR2015resistancekinome

Other posts related to, Cancer, Chemotherapy, Gleevec and Resistance on this Open Access Journal Include

Imatinib (Gleevec) May Help Treat Aggressive Lymphoma: Chronic Lymphocytic Leukemia (CLL)

Treatments for Acute Leukemias [2.4.4A]

Therapeutic Implications for Targeted Therapy from the Resurgence of Warburg ‘Hypothesis’

Hematologic Malignancies [6.2]

Overview of Posttranslational Modification (PTM)

Novel Modeling Methods for Genomic Data Analysis & Evolutionary Systems Biology to Design Dosing Regimens to Minimize Resistance

Mechanisms of Drug Resistance

Using RNA-seq and targeted nucleases to identify mechanisms of drug resistance in acute myeloid leukemia

An alternative approach to overcoming the apoptotic resistance of pancreatic cancer

Resistance to Receptor of Tyrosine Kinase

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