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Divergent Functions of ERK Substrate Binding Domains in Pathogenesis of Myeloproliferative Neoplasms

Award Number: R01CA283396
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/06/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Divergent Functions of ERK Substrate Binding Domains in Pathogenesis of Myeloproliferative Neoplasms - PROJECT SUMMARY/ABSTRACT The Ras/MAPK pathway is activated in 85% of human cancer. Nevertheless, attempts to target Ras/MAPK signaling have produced only limited efficacy. We hypothesize that one reason for the failure to successfully target this pathway is that the targeting efforts have focused on the active sites of kinases in this cascade, which has failed to provide long-lasting benefit. We hypothesize that the failure of this approach results from two causes: 1) Active site inhibitors, which resemble adenosine triphosphate (ATP), must overcome the exceedingly high cytosolic ATP levels in cancer cells; and 2) critical kinases in this cascade (e.g., ERK1/2) have distinct substrate interactions domains that can perform antagonistic roles in regulating cancer progression. Consequently, active-site focused inhibition is akin to simultaneous depression of the accelerator and brake pedals of an automobile. We hypothesize that a more successful approach will be to develop inhibitors which preserve kinase activity, but divert it exclusively to “brake pedal” substrates. In support, we have demonstrated that the two substrate binding domains of ERK2, termed the D and DPB domains, play opposing roles in the pathogenesis of JAK2-kinase driven myeloproliferative neoplasms (MPN). Indeed, the DBP and D domains act like brake and accelerator pedals, opposing and promoting disease progression, respectively. Consequently, pharmacologic attenuation of the accelerator pedal (D-domain) or its substrates should impair tumor progression more potently than active site inhibition, because it selectively interferes with the disease promoting activity of ERK2, while preserving the tumor suppressive function of the DBP-domain. While we have compelling evidence for the opposing roles of the ERK2-D and DBP domains, the molecular basis for their action remains unclear and this is an impediment to developing effective, pharmacologic interventions focused on the ERK2 D domain. We now seek to address this gap in knowledge according to the following aims. We will: 1) Assess the generality of the opposing functions of the ERK2-D and DBP domains in the pathogenesis of distinct MPN subtypes; 2) Understand the mechanistic basis by which the ERK2-D and DBP domains exert their distinct functions; and 3) Assess the efficacy of pharmacologic targeting of the ERK2-D domain and/or its targets in inhibiting cancer progression. Through these efforts we expect to bring new insights into the role of ERK2 substrate binding modules in regulating cancer progression and how to exploit this information therapeutically. While we begin with MPN, these findings may have far reaching implications for other Ras/MAPK driven cancers.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $707,044 )
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	3	7/1/2025	NON-COMPETING CONTINUATION	$707,044
														Subtotal = $707,044

Issue Date FY: 2024 ( Subtotal = $671,691 )
2024	2024	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	2	6/20/2024	NON-COMPETING CONTINUATION	$671,691
														Subtotal = $671,691

Issue Date FY: 2023 ( Subtotal = $707,046 )
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	1	7/6/2023	NEW	$707,046
														Subtotal = $707,046

Grand Total All Awards = $2,085,781

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Divergent Functions of ERK Substrate Binding Domains in Pathogenesis of Myeloproliferative Neoplasms

Award Number: R01CA283396

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/06/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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