Reference Detail

Ref Type

Journal Article

PMID

(38371625)

Authors

Fultang N, Schwab AM, McAneny-Droz S, Grego A, Rodgers S, Torres BV, Heiser D, Scherle P, Bhagwat N

Title

PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Frontiers in oncology	14		2024	1343004	Front Oncol

URL

Abstract Text

MCL1 is a member of the BCL2 family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. We previously described PRT1419, a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies. To identify novel biomarkers that predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using gene dependency data generated from CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with damaging PBRM1 mutations displayed a strong dependency on MCL1. PBRM1 (BAF180), is a chromatin-targeting subunit of mammalian pBAF complexes. PBRM1 is frequently altered in various cancers particularly ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We observed potent inhibition of tumor growth and induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not PBRM1-WT. Depletion of PBRM1 in PBRM1-WT ccRCC cell lines induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming cells for caspase-mediated apoptosis following MCL1 inhibition. Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT1419 synergized with both agents to potently inhibit tumor growth in PBRM1-loss ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PBRM1 inact mut	clear cell renal cell carcinoma	predicted - sensitive	PRT2527	Preclinical - Cell culture	Actionable	In a preclinical study, PRT2527 inhibited spheroid growth in clear cell renal cell carcinoma cell lines harboring inactivating PBRM1 mutations in culture (PMID: 38371625).	38371625
PBRM1 inact mut	clear cell renal cell carcinoma	sensitive	Pazopanib + PRT1419	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of PRT1419 and Votrient (pazopanib) synergistically inhibited spheroid growth of clear cell renal cell carcinoma cell lines harboring inactivating PBRM1 mutations in culture (PMID: 38371625).	38371625
PBRM1 inact mut	clear cell renal cell carcinoma	sensitive	Everolimus + PRT1419	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of PRT1419 and Afinitor (everolimus) synergistically inhibited spheroid growth of clear cell renal cell carcinoma cell lines harboring inactivating PBRM1 mutations in culture (PMID: 38371625).	38371625
PBRM1 inact mut VHL loss	clear cell renal cell carcinoma	sensitive	Belzutifan + PRT1419	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of PRT1419 and Welireg (belzutifan) inhibited tumor growth of a clear cell renal cell carcinoma cell line xenograft model harboring an inactivating PBRM1 mutation and with loss of VHL (PMID: 38371625).	38371625
PBRM1 loss	lung cancer	sensitive	PRT1419 + Sunitinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of PRT1419 and Sutent (sunitinib) inhibited tumor growth and tumor re-growth in a lung cancer cell line xenograft model with loss of PBRM1 (PMID: 38371625).	38371625
PBRM1 loss	lung cancer	sensitive	PRT2527 + Sunitinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of PRT2527 and Sutent (sunitinib) inhibited tumor growth and tumor re-growth in a lung cancer cell line xenograft model with loss of PBRM1 (PMID: 38371625).	38371625
PBRM1 loss	lung cancer	sensitive	PRT2527	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PRT2527 inhibited tumor growth in a lung cancer cell line xenograft model with loss of PBRM1 (PMID: 38371625).	38371625
PBRM1 inact mut	clear cell renal cell carcinoma	sensitive	Cabozantinib + PRT1419	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of PRT1419 and Cometriq (Cabometyx, cabozantinib) synergistically inhibited spheroid growth of clear cell renal cell carcinoma cell lines harboring inactivating PBRM1 mutations in culture (PMID: 38371625).	38371625
PBRM1 inact mut	clear cell renal cell carcinoma	sensitive	PRT1419	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PRT1419 inhibited proliferation and induced apoptosis in clear cell renal cell carcinoma cells lines harboring inactivating PBRM1 mutations in culture, and inhibited tumor growth in a cell line xenograft model (PMID: 38371625).	38371625
PBRM1 inact mut	clear cell renal cell carcinoma	sensitive	PRT1419 + Sunitinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of PRT1419 and Sutent (sunitinib) synergistically inhibited spheroid growth of clear cell renal cell carcinoma cell lines harboring inactivating PBRM1 mutations in culture (PMID: 38371625).	38371625