Sensitivity of imatinib-resistant T315I BCR-ABL CML to a synergistic combination of ponatinib and forskolin treatment

Abstract

Tyrosine kinase inhibitors (TKIs) have dramatically improved the life expectancy of patients suffering from chronic myeloid leukemia (CML); however, patients will eventually develop resistance to TKI therapy or adverse side effects due to secondary off-target mechanisms associated with TKIs. CML patients exhibiting TKI resistance are at greater risk of developing an aggressive and drug-insensitive disease. Drug-resistant CML typically arises in response to spontaneous mutations within the drug binding sites of the targeted oncoproteins. To better understand the mechanism of drug resistance in TKI-resistant CML patients, the BCR-ABL transformed cell line KCL22 was grown with increasing concentrations of imatinib for a period of 6 weeks. Subsequently, a drug-resistant derivative of the parental KCL22 cell line harboring the T315I gatekeeper mutation was isolated and investigated for TKI drug sensitivity via multi-agent drug screens. A synergistic combination of ponatinib- and forskolin-reduced cell viability was identified in this clinically relevant imatinib-resistant CML cell line, which also proved efficacious in other CML cell lines. In summary, this study provides new insight into the biological underpinnings of BCR-ABL-driven CML and potential rationale for investigating novel treatment strategies for patients with T315I CML.

Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase

“…K562 is a CML line which is positive for the Bcr‐Abl1 fusion gene. KCL22 is an imatinib‐sensitive CML cell line and KCL22‐IR is an imatinib‐resistant cell line, which contains the T315I mutation …”

“…KCL22 is an imatinib-sensitive CML cell line and KCL22-IR is an imatinib-resistant cell line, which contains the T315I mutation. [22] In general, there is ap ositive correlation between the percent inhibition of ABL1 enzymatic activity and BCR-ABL-driven CML cell line proliferation inhibition. The 4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenylamine-containing compounds are all potent inhibitors of CML cell lines with IC 50 valuesi nt he sub-nanomolar or single-digit nanomolar range.…”

“…Herein we report alkynyl aminoisoquinolines and aminonaphthyridines analogues that are active against the BCR‐ABL1 enzyme, as well as ABL1 with T315I and E255K point mutations. These compounds also inhibit the proliferation of CML cells lines K562, KCL22, and KCL22‐IR, the latter of which is an imatinib‐resistant cell line …”

“…These compounds also inhibitt he proliferation of CML cells lines K562, KCL22, and KCL22-IR, the latter of which is an imatinib-resistant cell line. [20][21][22]…”

Tyrosine Kinase Inhibitors and Phosphatases: Overcoming the BCR-ABL T315I Mutation in CML with a Synergistic Combination of Ponatinib and Forskolin

“…When investigated, ponatinib and forskolin (PF) demonstrated a synergistic effect in a highly imatinib-resistant T315I BCR-ABL CML cell line. Used in combination with 20 μM of forskolin, ponatinib IC50 concentrations were attained at 0.5 nM [24]. Achieving such potency towards T315I positive CML may warrant in vivo and clinical investigation into whether such a combination possesses clinical value over standard ponatinib therapy.…”