Biology subjects

Nangia, V.

Publications and source records attributed to Nangia, V..

5 recordsLinked to original sources

bioRxiv2026

Targeted therapy-induced chromosomal instability dictates mitotic dependency on Aurora Kinase A

Targeted therapies eliminate cancer cells by inhibiting oncogenic signaling; however, tumor cells often evade cytotoxicity through proteomic and epigenetic reprogramming that enables survival. These adaptive responses may create collateral cellular stresses, such as DNA damage, that can be therapeutically exploited. When unresolved, DNA damage leads to chromosomal instability (CIN), a potential source of vulnerability. Whether KRAS inhibition induces DNA damage or CIN in KRAS-mutant non-small cell lung cancer (NSCLC) has not been established. Here, we show that the KRASG12C inhibitor LY3499446 induces CIN in KRAS-mutant NSCLC cell lines. A targeted compound screen revealed that the extent of CIN induction by KRASG12C inhibition strongly correlates with therapeutic synergy with the selective Aurora kinase A inhibitor LSN3321213. Mechanistically, KRASG12C inhibition stabilizes cyclin B1 during mitosis through activation of mitotic ATR/ATM signaling. In the presence of Aurora Kinase A inhibition, cyclin B1 stabilization delays mitotic exit and diverts cell fate from mitotic slippage or division toward mitotic catastrophe. Together, our findings identify CIN as a predictive marker of response to combined KRASG12C and Aurora Kinase A inhibition, providing mechanistic rationale to enhance the therapeutic window of AURKA inhibitors when used with targeted therapies.

cancer biology↗

bioRxiv2025

MAPK and mTORC1 signaling converge on Cyclin D to enable cell-cycle re-entry in melanoma persister cells

Resistance to targeted therapy in BRAF-mutant melanomas can arise from drug-tolerant persister cells, which can non-genetically escape drug-induced quiescence to resume proliferation. To investigate how melanoma cells escape drug to re-enter the cell cycle within 3-4 days of BRAF and MEK inhibition, we computationally reconstructed single-cell lineages from time-lapse imaging data, linking key signaling pathways to cell-cycle fate outcomes. We found that ERK reactivation, while necessary, is insufficient for cell-cycle re-entry under MAPK inhibition. Instead, mTORC1 emerged as an additional critical mediator, enhancing translation and cell growth in cells destined for drug escape. We further found that ERK and mTORC1 signaling converge to produce Cyclin D1 protein levels, a key bottleneck for cell-cycle re-entry. Using CRISPR to tag endogenous Cyclin D1, we found that future escapees markedly upregulate Cyclin D1 at least 15 hours prior to drug escape, compared to non-escapees. Importantly, this early upregulation enables accurate prediction of future escapees from non-escapees, underscoring how differences in Cyclin D1 accumulation precede and govern the timing and likelihood of cell-cycle re-entry in persister cells. Our findings suggest that variability in ERK and mTORC1 activity underlies the heterogeneous Cyclin D1 levels observed, influencing the proliferative potential of persister cells and ultimately shaping the diverse cell-cycle behaviors observed under drug treatment. Cyclin D1 protein therefore emerges as both a critical biomarker and a therapeutic target for preventing cell-cycle re-entry in BRAF/MEK-treated melanoma. One Sentence SummaryCyclin D1 accumulation, driven by the integration of heterogeneous MAPK and mTORC1 signaling, is a critical bottleneck for cell-cycle re-entry in drug-treated melanoma cells.

systems biology↗

bioRxiv2024

BRAF V600 and ErbB inhibitors directly activate GCN2 in an off-target manner to limit cancer cell proliferation

Targeted kinase inhibitors are well known for their promiscuity and off-target effects. Herein, we define an off-target effect in which several clinical BRAFV600 inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4. Blocking this off-target effect by co-drugging with a GCN2 inhibitor in A375 melanoma cells causes enhancement rather than suppression of cancer cell outgrowth, suggesting that the off-target activation of GCN2 is detrimental to these cells. This result is mirrored in PC9 lung cancer cells treated with erlotinib, an EGFR inhibitor, that shares the same off-target activation of GCN2. Using an in silico kinase inhibitor screen, we identified dozens of FDA-approved drugs that appear to share this off-target activation of GCN2 and ATF4. Thus, GCN2 activation may modulate the therapeutic efficacy of some kinase inhibitors, depending on the cancer context.

cancer biology↗

bioRxiv2023

Multiple cancer types rapidly escape from multiple MAPK inhibitors to generate mutagenesis-prone subpopulations

Many cancers harbor pro-proliferative mutations of the mitogen-activated protein kinase (MAPK) pathway and many targeted inhibitors now exist for clinical use, but drug resistance remains a major issue. We recently showed that BRAF-driven melanoma cells treated with BRAF inhibitors can non-genetically adapt to drug within 3-4 days to escape quiescence and resume slow proliferation. Here we show that this phenomenon is not unique to melanomas treated with BRAF inhibitors but rather is widespread across many clinical MAPK inhibitors and cancer types driven by EGFR, KRAS, and BRAF mutations. In all treatment contexts examined, a subset of cells can escape drug-induced quiescence within four days to resume proliferation. These escapee cells broadly experience aberrant DNA replication, accumulate DNA lesions, spend longer in G2-M cell cycle phases, and mount an ATR-dependent stress response. We further identify the Fanconi anemia (FA) DNA repair pathway as critical for successful mitotic completion in escapees. Long-term cultures, patient samples, and clinical data demonstrate a broad dependency on ATR- and FA-mediated stress tolerance. Together, these results highlight the pervasiveness with which MAPK-mutant cancers are able to rapidly escape drug and the importance of suppressing early stress tolerance pathways to potentially achieve more durable clinical responses to targeted MAPK pathway inhibitors.

cancer biology↗

bioRxiv2021

APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

cancer biology↗