# A Convergent Node in Melanoma to Block Multiple Oncogenic Pathways Simultaneously

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $519,100

## Abstract

ABSTRACT
Despite recent major advances in targeted therapy for melanoma, the nearly universal eventual
acquisition of drug resistance remains a major hurdle that prevents durable gains in patient
survival. To address this critical unmet need, we have recently used patient samples and model
systems to identify S6K1 as a critical counter-resistance therapy target that lies at the
downstream convergence point of the MAPK, CDK4/6, and PI3K pathways. Importantly, these
are the primary drivers of both melanomagenesis and of known BRAF and MEK inhibitor
resistance mechanisms, positing S6K1, an understudied drug target, as a potential broad-use
salvage and/or frontline therapy. Our preliminary data is consistent with this hypothesis, as
pharmacological S6K1 inhibition reversed MAPK inhibitor resistance in several drug and genetic
contexts. Our central hypothesis is that understanding the mechanistic basis and clinical
applicability of S6K1 inhibition in melanoma will allow for improved design of next-generation
S6K1 inhibitors and combination therapies, as well as a deeper functional understanding of drug
resistance mechanisms operating through and downstream of S6K1. Specific Aim 1 will focus
on developing S6K1 as a key drug target in the contexts of both drug resistance and tumor
initiation, and its clinical relevance will be interrogated in a series of clinical biopsies. Specific
Aim 2 will determine the oncogenic mechanisms downstream of S6K1, with distinct focuses on
its impact on cell cycle and metabolism. Overall, successful completion of this study will provide
an evidential basis for S6K1 as a promising broad-use therapeutic target, with a mechanistic
underpinning to further refine future designs and uses of pharmacological S6K inhibitors.

## Key facts

- **NIH application ID:** 10028343
- **Project number:** 1R01CA251608-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Lawrence Kwong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $519,100
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10028343

## Citation

> US National Institutes of Health, RePORTER application 10028343, A Convergent Node in Melanoma to Block Multiple Oncogenic Pathways Simultaneously (1R01CA251608-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10028343. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*