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Functional impact, mechanistic role, and targetability of ROS1 aberrations in cancer

Award Number: R01CA233495
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/03/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Functional impact, mechanistic role, and targetability of ROS1 aberrations in cancer - PROJECT SUMMARY Chromosomal rearrangements of the proto-oncogene ROS1 produce constitutively active ROS1 kinase-fusion proteins that are established as druggable pathogenic drivers in human cancer. Currently, this is the only validated mechanism of aberrant ROS1 activation in oncogenesis. ROS1 is targetable with multiple tyrosine kinase inhibitors (TKI), and significant tumor regression is observed in ROS1-fusion positive patients who are treated with targeted TKI. Cancer genome sequencing studies reveal numerous ROS1 somatic mutations but their impact on catalytic function has not been tested, prompting new questions about ROS1-driven cancer pathogenesis. Further, the mechanistic role of ROS1 carboxy terminus in governing intra- or intermolecular regulation is unknown. Broadly, these gaps in knowledge, regarding regulation of ROS1 and its structure-function relationships, impede meaningful utilization of accumulating cancer genome data. Our overall hypothesis is that characterization of ROS1 tyrosine kinase and carboxy-terminal domains through the lens of somatic mutations will unveil biological underpinnings of receptor regulation, and contribute to translation of cancer genomic data. We will experimentally address this hypothesis by answering the following questions: (1) Do cancer-associated ROS1 tyrosine kinase domain (TKD) mutations activate catalytic function, and is this sufficient for neoplastic transformation or metastatic dissemination, either alone or in cooperation with hotspot oncoproteins? Preliminary data offer proof of concept that an engineered activating ROS1 TKD mutation transforms cells, and is targetable with ROS1-TKI. We will test if twenty prioritized somatic ROS1 TKD mutations enhance catalytic function, induce cellular transformation and tumor formation, and assess their drug sensitivity patterns. (2) How does the carboxy-terminal domain (CTD) of ROS1 regulate protein stability and TKI-induced protein downregulation? Our pilot data show that (a) ROS1 is ubiquitinated, (b) catalytically inactive ROS1 undergoes proteasome-assisted degradation, and (c) regulatory motifs within ROS1 CTD are likely involved. Engineered ROS1 CTD truncations retain catalytic activity but exhibit longer protein half-life under steady state and TKI-treated conditions. In Aim 2, we will map ubiquitination sites, track the cellular fate of ubiquitinated ROS1, and assess impact of somatic CTD mutations on ROS1 function. Cumulatively, I am confident that these studies will provide novel mechanistic insight into ROS1, and potentially facilitate clinical translation of genomic sequencing data for expanded impact of ROS1-TKI.


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: 2024 ( Subtotal = $281,116 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	5	2/27/2024	NON-COMPETING CONTINUATION	$266,320
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$14,796
														Subtotal = $281,116

Issue Date FY: 2023 ( Subtotal = $289,993 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	4	2/16/2023	NON-COMPETING CONTINUATION	$289,993
														Subtotal = $289,993

Issue Date FY: 2022 ( Subtotal = $304,984 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	3	3/8/2022	NON-COMPETING CONTINUATION	$266,319
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	002	3	6/29/2022	NON-COMPETING CONTINUATION	$14,991
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	001	3	5/9/2022	NON-COMPETING CONTINUATION	$23,674
														Subtotal = $304,984

Issue Date FY: 2021 ( Subtotal = $295,911 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	2	2/3/2021	NON-COMPETING CONTINUATION	$295,911
														Subtotal = $295,911

Issue Date FY: 2020 ( Subtotal = $295,911 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	1	3/5/2020	NEW	$295,911
														Subtotal = $295,911

Grand Total All Awards = $1,467,915

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Functional impact, mechanistic role, and targetability of ROS1 aberrations in cancer

Award Number: R01CA233495

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/03/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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